Endotoxin antagonists appear to slow metabolism.

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rockarolla

rockarolla

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Sorry for the delay - better late than never. ;) Below is an incomplete list of some TLR4 antagonists together with agonists like mercury.
 
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rockarolla

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There are some pros and cons as you'll see below.

Good overview paper:

Inhibition of Toll-Like Receptor Signaling as a Promising Therapy for Inflammatory Diseases: A Journey from Molecular to Nano Therapeutics
Inhibition of Toll-Like Receptor Signaling as a Promising Therapy for Inflammatory Diseases: A Journey from Molecular to Nano Therapeutics
Although, significant efforts have been made in developing different kinds of new TLR inhibitors/antagonists, only limited numbers of them have undergone clinical trials, and none have been approved for clinical uses to date. Nevertheless, these findings and continuous studies of TLR inhibition highlight the pharmacological regulation of TLR signaling, especially on multiple TLR pathways, as future promising therapeutic strategy for various inflammatory and autoimmune diseases.
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Due to their capability of recognizing a variety of PAMPs, TLRs play a critical role in fighting against pathogen infection (Mogensen, 2009). The first identified TLR4 can detect a wide range of Gram-negative bacteria by recognizing and responding to the coating molecules on the bacteria cell wall—lipopolysaccharide (LPS). TLR2 (in conjunction with either TLR1 or TLR6) primarily recognizes lipoproteins/lipopeptides and glycolipids from various pathogens including microbes and fungi. TLR5 is the only TLR that identifies a protein ligand—flagellin from nearly all flagellated bacteria. On the other hand, the endosomal TLRs (TLR3, and TLR7-TLR9) are mainly responsible for the recognition of nucleic acid ligands, including dsRNA, ssRNA, and CpG-DNA, from viral and intracellular bacterial infection. Therefore, activation of TLRs by engaging with these PAMPs allows the host to combat invading pathogens. In fact, TLR agonists have long been considered as vaccine adjuvants to boost the immune system to eliminate viral infections and most recently fight cancer (O'Neill et al., 2009; Hedayat et al., 2011).
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The expression of TLRs can be found in a variety of immune cells (e.g., dendritic cells, monocytes, macrophages, and B lymphocytes) and non-immune cells (e.g., epithelial cells, endothelial cells, and fibroblasts; Takeda et al., 2003).


Usefulness of oral administration of lipopolysaccharide(endotoxin) for disease prevention through the induction of priming in macrophages
Usefulness of Oral Administration of Lipopolysaccharide for Disease Prevention Through the Induction of Priming in Macrophages
Coley's toxin has been used as an immunotherapy in patients with cancer since 1891, and this practice is continued even today because of positive experience gained from more than 120 yearsn of use. Coley's toxin contains a mixture of dead Serratia marcescens and Streptococcus pyogenes bacteria and is known as a LPS-containing therapeutic agent (17).
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Considering the purposiveness of the LPS, we believe that LPS may be regarded as a micronutrient with some medicinal properties for the human body rather than as an endotoxin. For example, epidemiological studies show that LPS is inversely correlated with risk of allergic disease (hygiene hypothesis) (23). The knockout of the gene of the LPS receptor in mice results in low resistance to infection (24). Moreover, the amount of LPS in various foods indicates that some herbal Chinese medicines contain a few tens of micrograms of LPS per gram of dry weight (8), whereas health foods contain several micrograms. These data suggest that ingestion of a certain amount of LPS may be important for health maintenance.
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We have studied the preventative and curative effects on various diseases of oral administration of Pantoea agglomerans LPS, originally isolated from wheat flour. We observed several effects, such as protection from infectious diseases [bacterial and parasitic (toxoplasmosis)], improvement of diabetes and lipid metabolism (14), antiallergic properties in atopic dermatitis (13), an infection prophylaxis effect (25), and beneficial effects in cancer (26). LPS performs an important function in regulation of intestinal bacterial flora through the induction of bactericidal peptides (27). After oral administration, LPS is delivered to Paneth cells in intestinal crypts and induces production of bactericidal peptides defensins, such as regenerating islet-derived protein 3 gamma (28) and cryptdin-4 (29). According to the report of Masuda et al., cryptdin-4 has the ability to control the growth of pathogenic bacteria in the intestine (29).
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In a model of chronic stress based on daily dexamethasone injection in chicken, antibody production against a Salmonella vaccine was significantly decreased. Oral administration of P. agglomerans LPS improved the antibody titer against Salmonella in this chronic stress model (31). It was also shown that oral administration of LPS protects against steroidal withering of immune system organs: the spleen and bursa. These results indicate that oral administration of LPS saves immune cells from death caused by several types of stress.
Next Section

Conclusion – Macrophages and LPS for Maintaining Health

Macrophages recognize and eliminate oxidized lipids, denatured proteins, advanced glycation end-products, and dead cells. These are the true causative agents of chronic inflammation, which can lead to several diseases such as diabetes, arteriosclerosis, cancer, allergy, and dementia. As mentioned above, the essential role of macrophages in health maintenance is mainly believed to be the removal of waste products from the body. In accordance with this concept, we believe that a new paradigm should be adopted for health maintenance. For example, an outbreak of a disease may be the result of suppression of macrophage function that ensures elimination of waste products.
 
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Involvement of TLR2 and TLR9 in the anti-inflammatory effects of chlorogenic acid in Herpes Simplex Virus-1-infected microglia.
Involvement of TLR2 and TLR9 in the anti-inflammatory effects of chlorogenic acid in HSV-1-infected microglia - PubMed
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CGA could attenuate HSV(Herpes Simplex Virus)-induced TNF-α and IL-6 release into the supernatant. The mRNA levels of TNF-α and IL-6 were also significantly inhibited by CGA. The expression of NF-κB p65 increased significantly in the nucleus in HSV-1-stimulated microglia but could be reduced by CGA.
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CGA inhibits the inflammatory reaction in HSE(Herpes Simplex Virus Encephalitis) via the suppression of TLR2/TLR9-Myd88 signaling pathways.

Chlorogenic acid attenuates lipopolysaccharide-induced mice mastitis by suppressing TLR4-mediated NF-κB signaling pathway.
Chlorogenic acid attenuates lipopolysaccharide-induced mice mastitis by suppressing TLR4-mediated NF-κB signaling pathway - PubMed
The results showed that CGA significantly reduced TNF-α, IL-1β, and IL-6 production compared with LPS group. Besides, western blot analysis showed that CGA could inhibit the expression of TLR4 and the phosphorylation of NF-κB and IκB induced by LPS. These results suggested that anti-inflammatory effects of CGA against LPS-induced mastitis may be due to its ability to inhibit TLR4-mediated NF-κB signaling pathway. Therefore, CGA may be a potent therapeutic reagent for the prevention of the immunopathology encountered during Escherichia coli elicited mastitis.

TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis
TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis
Molecular recognition of minute amounts of circulating LPS (endotoxin) by the TLR4 receptor system, followed by receptor dimerization on the cell membrane, starts the cascade of protein-protein interactions leading to the production of pro-inflammatory cytokines and interferons, thus launching the inflammatory and immune responses.
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Intravenous administration of CGA protected C57BL/6 mice from septic shock after intraperitoneal LPS challenge [97]. At the dosage 3 mg/kg (CGA), the survival rate was increased up to 70%. In addition, the cytokine levels in blood of treated animals were decreased, too. In vitro, kinase assays demonstrated that MAPK activation was blocked by CGA, as well as auto-phosphorylation of IRAK4. Protein or mRNA levels of TNF-α, IL-1α, and HMGB-1 (high-mobility group box-1) in the peritoneal macrophages, induced by LPS, were also attenuated by CGA treatment.

Differential modulation of toll-like receptor agonists-induced iNOS expression by polyunsaturated and saturated fatty acids
https://www.tandfonline.com/doi/full/10.1080/09540105.2017.1326468
The present study investigated the effects of arachidic acid (ACA), which is a saturated fatty acid (SFA), and eicosapentanoic acid (EPA), which is polyunsaturated fatty acid (PUFA), on inflammation by modulating NF-κB activation and iNOS expression induced by TLRs agonists in murine macrophages. EPA suppressed NF-κB activation and iNOS expression induced by a lipopolysaccharide, macrophage-activating lipopeptide 2-kDa, and polyriboinosinic polyribocytidylic acid, but ACA did not. These results suggested that EPA can modulate TLR signaling pathways and subsequent chronic inflammatory responses, but ACA did not mediate these effects. All the results suggest that EPA is a promising novel agent for the treatment of inflammatory diseases.

Polyunsaturated Fatty Acids and Inflammation
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PUFA can interfere with pattern recognition receptors such as toll-like receptors (TLR) or nucleotide-binding oligodimerization domains (NOD). Upon stimulation with LPS, TLR-4, a cell membrane receptor, activates proinflammatory signalling cascade. While saturated fatty acids such as lauric acid facilitates its dimerization, numerous studies have observed that n-3 PUFA inhibit its activation (29,30).

Coenzyme Q10 supplementation downregulates the increase of monocytes expressing toll-like receptor 4 in response to 6-day intensive training in kendo athletes.
Coenzyme Q10 supplementation downregulates the increase of monocytes expressing toll-like receptor 4 in response to 6-day intensive training in kendo athletes - PubMed

Lithium ameliorates lipopolysaccharide-induced microglial activation via inhibition of toll-like receptor 4 expression(TLR4) by activating the PI3K/Akt/FoxO1 pathway
Lithium ameliorates lipopolysaccharide-induced microglial activation via inhibition of toll-like receptor 4 expression by activating the PI3K/Akt/FoxO1 pathway
Lithium significantly inhibited LPS-induced microglial activation and pro-inflammatory cytokine production. Further analysis showed that lithium could activate PI3K/Akt signaling. Analyses of the associated signaling pathways demonstrated that the lithium pretreatment led to the suppression of LPS-induced toll-like receptor 4 (TLR4) expressions via the PI3K/Akt/FoxO1 pathway.

Magnesium Decreases Inflammatory Cytokine Production: A Novel Innate Immunomodulatory Mechanism
Magnesium Decreases Inflammatory Cytokine Production: A Novel Innate Immunomodulatory Mechanism
Short-term exposure to a clinically effective MgSO4 concentration in vitro substantially reduced the frequency of neonatal monocytes producing TNF-α and IL-6 under constitutive and TLR-stimulated conditions, decreasing cytokine gene and protein expression, without influencing cell viability or phagocytic function. In summary, MgSO4 reduced cytokine production in intrapartum women, term and preterm neonates, demonstrating effectiveness in those at risk for inflammation-associated adverse perinatal outcomes. By probing the mechanism of decreased cytokine production, we found that the immunomodulatory effect was mediated by magnesium and not the sulfate moiety, and it was reversible. Cellular magnesium content increased rapidly upon MgSO4 exposure, and reduced cytokine production occurred following stimulation with different TLR ligands as well as when magnesium was added after TLR stimulation, strongly suggesting that magnesium acts intracellularly. Magnesium increased basal IκBα levels, and upon TLR stimulation was associated with reduced NF-κB activation and nuclear localization. These findings establish a new paradigm for innate immunoregulation, whereby magnesium plays a critical regulatory role in NF-κB activation, cytokine production, and disease pathogenesis.

The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain
The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain
Naltrexone simultaneously has an antagonist effect on non-opioid receptors (Toll-like receptor 4 or TLR4) that are found on macrophages such as microglia...

Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism
Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism
Increased bacterial lipopolysaccharide (LPS) triggers a toll-like receptor 4 (TLR4) mediated pro-inflammatory cascade in immune cells (monocytes, macrophages and Kupffer cells), leading to the activation of downstream signaling pathways, such as nuclear factor kappa β (NF-kΒ) and mitogen-activated protein kinase (MAPK), which can lead to inflammation driven by cytokines such as TNF-a and IL-6.37 Of the SCFA produced in the colon, butyrate appears to be the most important regulator of TJP and has been shown to enhance intestinal barrier function through increased expression of claudin-1 and Zonula Occludens-1 (ZO-1) and occludin redistribution; proteins which are critical components of the tight junction assembly.38 Butyrate has been shown to reverse the aberrant expression of ZO-1 and decrease LPS translocation leading to inhibition of macrophage activation, pro-inflammatory cytokine production and neutrophil infiltration resulting in reduced hepatic liver injury in rats.39 Further work is urgently needed in human models to determine whether SCFA play an important role in mucosal maintenance and integrity.

Blockade of Toll-Like Receptors (TLR2, TLR4) Attenuates Pain and Potentiates Buprenorphine Analgesia in a Rat Neuropathic Pain Model
Blockade of Toll-Like Receptors (TLR2, TLR4) Attenuates Pain and Potentiates Buprenorphine Analgesia in a Rat Neuropathic Pain Model

Antidepressants normalize elevated Toll-like receptor profile in major depressive disorder
Antidepressants normalize elevated Toll-like receptor profile in major depressive disorder
Abnormalities in Toll-like receptor (TLR) expression in depression have been inferred in part from observed increases in TLR4 levels in peripheral blood mononuclear cells (PBMCs) and postmortem brains of depressed and suicidal patients. Our previous study found differences in the TLR expression in PBMCs between healthy controls and patients with major depressive disorder. Normalization of increased TLR4 in PBMCs by cognitive behavior psychotherapy has been reported.
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TLR3, TLR4, TLR5, TLR7, TLR8, and TLR9 were expressed at elevated levels in patients with MDD(major depressive disorder) and were significantly decreased by treatment with antidepressants for 4 weeks. Antidepressant treatment completely normalized TLR3, TLR5, TLR7, TLR8, and TLR9 levels, whereas TLR1, TLR2, TLR4, and TLR6 were decreased to below normal levels.
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These findings suggest that antidepressant treatment exerts anti-inflammatory effects in patients with MDD(major depressive disorder) and identify TLR profiles as a predictor of response to antidepressant therapy. Further studies investigating the effects of manipulating individual TLRs on depression are needed to fully elucidate the underlying mechanism.
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This study has provided novel insights into relationships among TLR expression, antidepressants, and clinical response for a well-characterized MDD. Beyond confirming that the expression levels of certain TLRs are decreased in PBMCs among MDD patients, we have also described—to the best of our knowledge for the first time—distinctive effects of antidepressants on TLRs. In summary, the observed decrease in TLR expression and its association with treatment outcome in depressive patients implies a link between inflammation, depression, and treatment. Further animal studies are needed to test antidepressive effects using antagonists of specific TLRs.

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Effects of Two Weeks of High-intensity Interval Training (HIIT) on Monocyte TLR2 and TLR4 Expression in High BMI Sedentary Men
Effects of Two Weeks of High-intensity Interval Training (HIIT) on Monocyte TLR2 and TLR4 Expression in High BMI Sedentary Men
Two weeks of high-intensity intermittent exercise training increased VO2peak and total CD14+ monocyte TLR4 expression in a sedentary, high BMI population. There was no influence of training on the proportions of classical and pro-inflammatory monocyte subsets, but TLR4 expression in the majority of these monocyte subsets (apart from CD14++CD16+) was higher after the six training sessions.

Effect of strenuous exercise and ex vivo TLR3 and TLR4 stimulation on inflammatory gene expression in equine pulmonary leukocytes
Effect of strenuous exercise and ex vivo TLR3 and TLR4 stimulation on inflammatory gene expression in equine pulmonary leukocytes

Exercise Therapy Downregulates the Overexpression of TLR4, TLR2, MyD88 and NF-κB after Cerebral Ischemia in Rats
http://images.biomedsearch.com/2343...646400&Signature=Xe8WXRIQ9HR2yiOTOVf4YnWVdf4=

TLR4-Mediated Blunting of Inflammatory Responses to Eccentric Exercise in Young Women
TLR4-Mediated Blunting of Inflammatory Responses to Eccentric Exercise in Young Women
...these data suggest eccentric training may help to prevent TLR4 activation principally through NF-κB, and perhaps IRF3, downstream signaling in this population.

Exercise and Toll-like receptors.
https://www.ncbi.nlm.nih.gov/pubmed/17201071
Toll-like receptors (TLRs) are highly conserved trans-membrane proteins that play an important role in the detection and recognition of microbial pathogens. The key product of TLR signalling in antigen presenting cells is the production of inflammatory cytokines and proteins. The TLR pathway plays an important role in mediating whole body inflammation, which has been implicated in the development of chronic disease. An accumulation of chronic, low-grade inflammation is common in individuals that live a sedentary lifestyle; however, the mechanism underlying this connection is not fully understood. There is evidence to show that TLRs may be involved in the link between a sedentary lifestyle, inflammation, and disease. Recent studies have shown that both acute aerobic and chronic resistance exercise resulted in decreased monocyte cell-surface expression of TLRs. Furthermore, a period of chronic exercise training decreases both inflammatory cytokine production and the cell-surface expression of TLR4 on monocytes. These effects may contribute to post-exercise immunodepression and the reported higher susceptibility to infection in athletes.

Physical Exercise Reduces Circulating Lipopolysaccharide and TLR4 Activation and Improves Insulin Signaling in Tissues of DIO Rats
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046839/
 
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Screening of herbal extracts for TLR2- and TLR4-dependent anti-inflammatory effects
Screening of herbal extracts for TLR2- and TLR4-dependent anti-inflammatory effects
There is a growing interest in using natural extracts as possible new treatment strategies for inflammatory diseases. We therefore aimed at identifying herbal extracts that affect inflammatory signaling pathways through toll-like receptors (TLRs), TLR2 and TLR4.
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Ethanolic extracts which showed the highest anti-inflammatory potential, up to a complete inhibition of pro-inflammatory cytokine production were Castanea sativa leaves, Cinchona pubescens bark, Cinnamomum verum bark, Salix alba bark, Rheum palmatum root, Alchemilla vulgaris plant, Humulus lupulus cones, Vaccinium myrtillus berries, Curcuma longa root and Arctostaphylos uva-ursi leaves.
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Moreover, all tested extracts mitigated not only TLR4, but also TLR2 signaling pathways. Seven of them additionally inhibited translocation of NF-κB into the nucleus. Two of the extracts showed impact on repolarization of pro-inflammatory M1-type to anti-inflammatory M2-type macrophages.
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In conclusion, we showed that numerous ethanolic herbal extracts mitigate TLR2- and TLR4-dependent signaling and downstream inflammation. Several of them are known as officinal plants, but the underlying molecular mechanisms of their anti-inflammatory effects are often ill-defined or unknown. TLR pathways are of fundamental relevance in diverse inflammatory diseases.
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Turmeric (Curcuma longa)–root
Our results suggest that TLR2/TLR4 signaling pathways are molecular targets of turmeric extract. This is supported by reports that show that turmeric and some of its compounds, especially curcumin and aromatic-turmerone, inhibit LPS-induced NF-κB activation, and expression of TLR4 and the downstream genes IL-1 receptor-associated kinase 1 (IRAK-1) and tumor necrosis factor receptor-associated factor 6 (TRAF-6) [52].

Structure–Activity Relationships of (+)-Naltrexone-Inspired Toll-like Receptor 4 (TLR4) Antagonists
https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b00426?src=recsys&journalCode=jmcmar
Activation of Toll-like receptors has been linked to neuropathic pain and opioid dependence. (+)-Naltrexone acts as a Toll-like receptor 4 (TLR4) antagonist and has been shown to reverse neuropathic pain in rat studies. We designed and synthesized compounds based on (+)-naltrexone and (+)-noroxymorphone and evaluated their TLR4 antagonist activities by their effects on inhibiting lipopolysaccharide (LPS) induced TLR4 downstream nitric oxide (NO) production in microglia BV-2 cells. Alteration of the N-substituent in (+)-noroxymorphone gave us a potent TLR4 antagonist. The most promising analog, (+)-N-phenethylnoroxymorphone ((4S,4aR,7aS,12bR)-4a,9-dihydroxy-3-phenethyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 1j) showed ∼75 times better TLR-4 antagonist activity than (+)-naltrexone, and the ratio of its cell viability IC50, a measure of its toxicity, to TLR-4 antagonist activity (140 μM/1.4 μM) was among the best of the new analogs. This compound (1j) was active in vivo; it significantly increased and prolonged morphine analgesia.

New Ideas for Helping Difficult Pain Patients
New Ideas for Helping Difficult Pain Patients
In a 2008 animal study, Largent-Milnes et al5 demonstrated that ultra–low dose naltrexone enhanced the effects of both intrathecal and oral oxycodone in the treatment of neuropathic pain caused by spinal nerve ligation. Hutchinson et al demonstrated that the toll-like receptor 4 (TLR4) is a key receptor for initiating microglial activation and maintaining neuropathic pain.6 In addition, the study suggested that TLR4 antagonists, naloxone and naltrexone, can prevent and reverse neuropathic pain. They concluded that naloxone “may be useful clinically to suppress glial activation, and suppress pain.”

Toll-like Receptor-Dependent Negative Effects of Opioids: A Battle between Analgesia and Hyperalgesia
Toll-like Receptor-Dependent Negative Effects of Opioids: A Battle between Analgesia and Hyperalgesia

Opioid activation of toll-like receptor 4 contributes to drug reinforcement.
Opioid activation of toll-like receptor 4 contributes to drug reinforcement - PubMed

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Higher monocyte expression of TLR2 and TLR4, and enhanced pro-inflammatory synergy of TLR2 with NOD2 stimulation in sarcoidosis.
Higher monocyte expression of TLR2 and TLR4, and enhanced pro-inflammatory synergy of TLR2 with NOD2 stimulation in sarcoidosis - PubMed
Sarcoidosis is an inflammatory disease of unknown etiology. However, an infectious cause has been proposed suggesting a role for pattern-recognition receptors, such as Toll-like receptors (TLRs) and nucleotide-binding domain, leucin-rich repeat containing family proteins (NLRs), in the pathogenesis.

OBJECTIVE:
Our aim was to investigate whether differences in TLR2 and TLR4 expression, and the response to TLR2, TLR4, and NOD2 stimulation, are associated with sarcoidosis.

MATERIALS AND METHODS:
Blood mononuclear cells from sarcoidosis patients (n = 24) and healthy subjects (n = 19) were incubated with the TLR2 ligands PGN and Pam3CSK4, the TLR4 ligand LPS, the NOD2 ligand MDP, or medium alone. After 16 h, monocyte TLR2 and TLR4 expression and cytokine secretion, including TNFalpha, IL-1 beta, IL-6, IL-8, IL-10, and IL-12p70, were measured using flow cytometry and cytometric bead array.

RESULTS:
TLR2 and TLR4 expression at baseline was significantly higher in patients. Combined TLR2 and NOD2 stimulation induced a four-fold higher secretion of TNFalpha and a 13-fold higher secretion of IL-1 beta in patients. Additionally, there was a synergistic effect of TLR2 with NOD2 stimulation on induction of IL-1 beta in patients, whereas IL-10 was synergistically induced in healthy subjects.

CONCLUSION:
Increased TLR expression and enhanced secretion of pro-inflammatory cytokines after combined TLR2 and NOD2 stimulation may be related to the pathogenesis of sarcoidosis.

Expression of toll-like receptor 2 and 4 is increased in the respiratory epithelial cells of chronic idiopathic interstitial pneumonia patients.
Expression of toll-like receptor 2 and 4 is increased in the respiratory epithelial cells of chronic idiopathic interstitial pneumonia patients - PubMed

Fungal cell wall agents and bacterial lipopolysaccharide in organic dust as possible risk factors for pulmonary sarcoidosis
Fungal cell wall agents and bacterial lipopolysaccharide in organic dust as possible risk factors for pulmonary sarcoidosis - Journal of Occupational Medicine and Toxicology

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Ketamine(Ketamine - Wikipedia ) Suppresses Intestinal TLR4 Expression and NF-κB Activity in Lipopolysaccharide-treated Rats
Ketamine Suppresses Intestinal TLR4 Expression and NF-κB Activity in Lipopolysaccharide-treated Rats
 
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Effects of probiotics on Toll‑like receptor expression in ulcerative colitis rats induced by 2,4,6‑trinitro‑benzene sulfonic acid
Effects of probiotics on Toll‑like receptor expression in ulcerative colitis rats induced by 2,4,6‑trinitro‑benzene sulfonic acid
The present study aimed to investigate the regulatory effect of probiotics on the expression of Toll‑like receptors (TLRs) in an ulcerative colitis (UC) rat model, and to determine the role of probiotics in the underlying mechanisms through which UC develops and progresses in rat models. Rats were randomly allocated to one of the four following groups: i) The healthy control, ii) the model, iii) the Golden bifid treatment group, and iv) the TLR4 monoclonal antibody (TLR4mAb) intervention group. The UC rat model was established using 2,4,6‑trinitro‑benzene sulfonic acid. The general status and histological changes of rats were scored using the disease activity index and the histopathological scoring method, respectively. In these rats, the expression of TLR4 and TLR2 was measured using reverse transcription‑quantitative polymerase chain reaction. The expression of TLR4 and TLR2 in the model group was significantly higher than that in the healthy control group. However, when compared with the model rats, those that received either Golden bifid treatment or TLR4mAb intervention exhibited significantly decreased mRNA expression levels of TLR4 and TLR2 (P<0.05). The development of UC is characterized by an abnormal immune response in the intestines. Probiotics alleviated inflammatory reactions in rats with UC. The underlying mechanism of UC may be associated with the expression of TLRs and the subsequent release of inflammatory cytokines.

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Toll-like receptor 4 - innate immune regulator of neuroimmune and neuroendocrine interactions in stress and major depressive disorder:
Toll-like receptor 4: innate immune regulator of neuroimmune and neuroendocrine interactions in stress and major depressive disorder
Major depressive disorder (MDD) poses one of the highest disease burdens worldwide. Yet, current treatments targeting serotonergic and noradrenaline reuptake systems are insufficient to provide long-term relief from depressive symptoms in most patients, indicating the need for new treatment targets. Having the ability to influence behavior similar to depressive symptoms, as well as communicate with neuronal and neuroendocrine systems, the innate immune system is a strong candidate for MDD treatments. Given the complex nature of immune signaling, the main question becomes: What is the role of the innate immune system in MDD? The current review presents evidence that toll-like receptor 4 (TLR4), via driving both peripheral and central immune responses, can interact with serotonergic neurotransmission and cause neuroendocrine disturbances, thus integrating with widely observed hallmarks of MDD. Additionally, through describing the multi-directional communication between immune, neural and endocrine systems in stress, TLR4—related mechanisms can mediate stress-induced adaptations, which are necessary for the development of MDD.

Neuroinflammatory events - neuroinflammation and neurokine signaling in MDD:

Although immune signaling in the brain is comprised of signals from resident glial cells, peripheral to central immune communications and migration of peripheral cells into central compartments, it is important to note the phenotypic differences between different neuroinflammatory diseases. The term “Neuroinflammation” is commonly used to encompass increased immune activation in the CNS. However, the central nervous system (CNS) can take on different inflammatory states, and there is a distinction between the magnitude of immune responses in the CNS by varied causes. For example, neurodegenerative disorders including Alzheimer's and Parkinson's disease are characterized by widespread immune signaling in the CNS, oxidative stress, and increased immune trafficking into the brain, resulting in systemic inflammation accompanied with progressive damage (Heneka et al., 2014). On the other hand, acute and sub-maximal immune challenges such as that triggered by opioid exposure can also cause increased central immune signaling, but the resulting inflammatory response is of a much lower magnitude (Stevens et al., 2013). This sub-inflammatory state is attributed to the direct actions of opioids on CNS expressed toll-like receptor 4 (TLR4), since opioids readily cross the BBB, rather than the indirect peripheral to central immune response following bacterial infections (Hutchinson and Watkins, 2014; Jacobsen et al., 2014).

TLR4 activity can influence behavior and MDD

Using LPS as an agonist, peripheral TLR4 activation is sufficient to cause changes in motivational state and can trigger sickness behavior (Hines et al., 2013). Sickness behavior is characterized by increased anhedonia, lethargy, loss of locomotion and anorexia following immune challenges (Dantzer and Kelley, 2007). Once thought to stem from altered energy balance, it is clear that these immune signaling initiated behavioral adaptations are driven by specific cytokine-dependent signaling cascades (Dantzer, 2004). Thus, an immune stimulus can drive complex higher order behavioral adaptations, providing direct evidence for the link between the immune system and symptoms of depression.

Although the idea of sickness behavior may appear surprising since pathogens themselves are imperceptible by our classic sensory organs, it makes sense that the body needs to know when it encounters pathogens in order to make behavioral adjustments. Through reduction in locomotion, sickness behavior can promote recovery from the immune challenges. Sickness behavior can therefore be considered as adaptive since it promotes homeostasis within the conditions of the stressor (Dantzer and Kelley, 2007).
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Strong parallels can be drawn between sickness behavior and depressive behavior, namely reduced locomotion, anhedonia, and dysregulated sleep and food intake (McCusker and Kelley, 2013). Since MDD can be chronic and recurring, the question arises whether patients with MDD are just displaying chronic dysregulation in inflammation or immune signaling? Indeed, patients suffering from MDD display heightened circulating cytokine levels, indicative of increased immune signaling (Anisman and Hayley, 2012; Lichtblau et al., 2013). Furthermore, there is some evidence showing that celecoxib, an NSAID that inhibits COX-2, can improve depression scores as well as increase remission rates in patients receiving anti-depressants (Faridhosseini et al., 2014; Na et al., 2014). In rodent models, NSAID administration can improve depressive-like behavior, measured using the forced swim test and tail suspension tests (Maciel et al., 2013; Guan et al., 2014). Notably however, these studies indicate that the anti-depressive effect of NSAID requires a higher dose in order to achieve comparable results to SSRIs, and are more effective in immune stressor induced depressive-like behavior. Additionally, there is some debate about the efficacy of these treatments since NSAIDs can also reduce efficacy of SSRI treatment when given in conjunction, in both animals and patients (Warner-Schmidt et al., 2011). MDD thus appears to have an immune component, but the exact mechanisms behind this interaction require more investigation.

Diclofenac pretreatment modulates exercise-induced inflammation in skeletal muscle of rats through the TLR4/NF-κB pathway
http://www.nrcresearchpress.com/doi/10.1139/apnm-2016-0593#.XDDPrFwzaAY
These findings suggest that pretreatment with diclofenac may represent an effective tool to ameliorate the pro-inflammatory status induced by acute exercise in rat skeletal muscle possibly through an attenuation of the TLR4-NF-κB signaling pathway.

Obesity, Inflammation, Toll-Like Receptor 4 and Fatty Acids
Obesity, Inflammation, Toll-Like Receptor 4 and Fatty Acids
The toll-like receptor 4 (TLR4) signaling pathway is acknowledged as one of the main triggers of the obesity-induced inflammatory response. The aim of the present review is to describe the role that is played by the TLR4 signaling pathway in the inflammatory response and its modulation by saturated and omega-3 polyunsaturated fatty acids. Studies indicate that saturated fatty acids can induce inflammation by activating the TLR4 signaling pathway. Conversely, omega-3 polyunsaturated fatty acids, such as eicosapentaenoic acid and docosahexaenoic acid, exert anti-inflammatory actions through the attenuation of the activation of the TLR4 signaling pathway by either lipopolysaccharides or saturated fatty acids.
 
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Gliadin is an uncatalogued Toll-like receptor ligand
Gliadin is an uncatalogued Toll-like receptor ligand

Coeliac disease is caused by an immune response to the wheat family in a susceptible host. Gliadins are the major pathogenic constituent of wheat.
Gliadins are known to initiate the innate and the adaptive immune response. Toll-like receptors (TLRs) detect conserved structural motifs of micro-organisms and endogenous proteins.
TLR7 and TLR8 single-nucleotide polymorphism is associated with coeliac disease. Gliadin can activate the TLR signalling pathway in vitro.
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Toll-like receptors (TLRs) are the best-studied group of pattern recognition receptors, which play a critical role in the initiation of innate immunity through the recognition of pathogen- and damage-associated molecular patterns. Exogenous food-derived proteins are not yet recognised as TLR ligands. Gliadin can activate TLR signalling pathway in vitro. The existing evidence is suggestive of the direct contribution of gliadin and/or other wheat components to activating TLR signalling. However, the data available so far are controversial and are mainly focussed on TLR 2 and TLR4. It is hypothesised that gliadin is a direct ligand for one of the TLRs. If indeed gliadin is proven to be a direct ligand of TLRs, our understanding of the pathogenesis of gastrointestinal diseases, such as colorectal cancer, will also be greatly influenced. In order to fully appreciate the role of gliadin as a direct TLR ligand, it should be proven to interact physically with and bind to one or more of the TLR molecules. Furthermore, it should be documented that TLR pathway activation is the downstream effect of gliadin/TLR binding.

If indeed gliadin exerts its pathogenic contribution to CD via activating TLR signalling, it is conceivable that targeted inhibition of the pathway or the specific responsible TLR could be a novel, biologic, therapeutic approach to the disease. Alternatively, gliadin could be engineered in a way which does not interact with TLRs. Genetically modified wheat and other causative cereals could then be engineered and mass-produced for coeliac patients.

If gliadin is proven to be a TLR ligand, the question on the role of TLR signalling in the pathogenesis of major intestinal pathologies, that is, IBD and CRC, will be significantly affected. So far, the scientific community is interested in the contribution of microbiota to the pathogenesis of IBD and CRC. Although nutrigenomics has gained interest in recent years, it has never been fully appreciated to have an equally significant role in the pathogenesis of IBD and CRC. In fact, the nutrient and metabolite components of the intestinal lumen are not yet comprehensively catalogue

Toll-Like Receptor-Triggered Calcium Mobilization Protects Mice against Bacterial Infection through Extracellular ATP Release
Toll-Like Receptor-Triggered Calcium Mobilization Protects Mice against Bacterial Infection through Extracellular ATP Release
Extracellular ATP (eATP), released as a “danger signal” by injured or stressed cells, plays an important role in the regulation of immune responses, but the relationship between ATP release and innate immune responses is still uncertain. In this study, we demonstrated that ATP was released through Toll-like receptor (TLR)-associated signaling in both Escherichia coli-infected mice and lipopolysaccharide (LPS)- or Pam3CSK4-treated macrophages. This ATP release could be blocked completely only by N-ethylmaleimide (NEM), not by carbenoxolone (CBX), flufenamic acid (FFA), or probenecid, suggesting the key role of exocytosis in this process. Furthermore, LPS-induced ATP release could also be reduced dramatically through suppressing calcium mobilization by use of U73122, caffeine, and thapsigargin (TG).
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In addition, the secretion of interleukin-1β (IL-1β) and CCL-2 was enhanced significantly by ATP, in a time- and dose-dependent manner. Meanwhile, macrophage-mediated phagocytosis of bacteria was also promoted significantly by ATP stimulation.
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The activation of TLRs by given agonists induces the secretion of proinflammatory cytokines, chemokines, and type I interferon (IFN), such as tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein 1 (MCP-1), and IFN-β, to fight against invading pathogens and recruit peripheral lymphocytes to the site of infection (21). In the past decades, most studies have focused on the secretion of cytokines, chemokines, and interferon in TLR-mediated immune responses. Actually, extracellular nucleotides secreted by injured or infected cells also play important roles in the innate immune system. Understanding the cross talk between TLR and purinergic signaling represents a novel approach to better understand immune regulation.
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In this study, we demonstrate that ATP is released from immune cells during bacterial infection mainly through exocytosis by TLR-dependent intracellular calcium mobilization. eATP then facilitates macrophage-mediated phagocytosis and cytokine production to clear invading bacteria through activation of P2 receptors. Furthermore, we also provide evidence that ATP has a nonredundant role in promoting host survival from Escherichia coli-induced peritonitis. TLR signaling not only can be involved in inflammation responses through the typical mitogen-activated protein kinase (MAPK) pathway but also can regulate innate immune responses via increasing extracellular “danger signals,” such as eATP. Taken together, our findings show a novel role of TLR-triggered calcium mobilization in the upregulation of innate immune responses against bacterial infection through extracellular ATP release.

Macrophage-mediated phagocytosis is promoted significantly by ATP:

As the key immune cell in the innate immune system, macrophages can engulf and digest pathogens and participate in antigen presentation. Thus, we evaluated macrophage-mediated pathogen phagocytosis and chemotaxis in ATP-treated cells. As shown in Fig. 5A and andB,B, the phagocytosis of GFP-labeled bacteria by RAW 264.7 cells was increased by pretreatment of cells with ATP (100 μM), and the increased phagocytosis could be reduced by apyrase, PPADS, and suramin. Although the secretion of CCL-2 was promoted by ATP, macrophage-mediated chemotaxis was influenced little by ATP (data not shown). Taken together, our current data further confirm the positive regulation of macrophage-mediated phagocytosis by ATP.
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As a key “danger signal,” ATP has been investigated for a long time in terms of the regulation of immune responses, but most studies in the past few decades focused only on the function of ATP and its receptors. Recently, the physiological effect of extracellular ATP on NLRP3 inflammasome activation was investigated in the context of bacterial infection (16). Why and how ATP is released during bacterial infection are still unknown. In this study, we demonstrated that ATP could be released from infected or stressed cells via a calcium-dependent manner which was induced by TLR signaling. The released ATP could then upregulate innate immune responses in macrophages and enhance the host defense against bacterial infection through activating P2X and P2Y receptors. Therefore, we can hypothesize that bacterium-induced TLR signaling not only activates classic immune responses but also induces ATP release through calcium mobilization, which could also facilitate the immune cells in an autocrine and/or paracrine manner. Actually, the release of ATP seems to be more important to the immune system, because the activation of TLRs can transduce intracellular signaling only in immune cells, but ATP can easily deliver the alarm signal to neighboring cells in a very short time, in a manner which is even quicker and more extensive than cytokine production. Thus, the release of ATP can also be regarded as a kind of feedback regulatory loop that may be important in protecting the host from bacterial infection (Fig. 6D). Our data broaden the understanding of eATP as a danger signal in the host defense against bacterial infection, which shows great potential for purinergic signaling in antibacterial drug discovery.
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ATP release was activated by LPS, and this activation could be inhibited dramatically by U73122, caffeine, and TG. These data suggested that LPS-induced ATP release is strongly associated with calcium mobilization, so we further appraised the effects of U73122, caffeine, and TG on LPS-induced calcium mobilization (Fig. 2C). Calcium mobilization was increased in LPS-treated cells and could be blocked almost entirely by these inhibitors.


Quercetin negatively regulates TLR4 signaling induced by lipopolysaccharide through Tollip expression.
Quercetin negatively regulates TLR4 signaling induced by lipopolysaccharide through Tollip expression - PubMed
Polyphenolic compounds have been regarded as one of the most promising dietary agents for the prevention and treatment of inflammation-related chronic diseases; however, the anti-inflammatory activities of flavonoids, such as quercetin, are not completely characterized, and many features remain to be elucidated. In this study, we showed the molecular basis for the downregulation of TLR4 signal transduction by quercetin. Quercetin markedly elevated the expression of the Toll-interacting protein, a negative regulator of TLR signaling. Lipopolysaccharide-induced expression of cell surface molecules (CD80, CD86, and MHC class I/II) and production of pro-inflammatory cytokines (tumor necrosis factor-α, IL-1β, IL-6, and IL-12p70) were inhibited by quercetin, and this action was prevented by Toll-interacting protein silencing. In addition, quercetin-treated macrophages inhibited lipopolysaccharide-induced activation of mitogen-activated protein kinases, such as extracellular signal-regulated kinase 1/2, p38, and c-Jun N-terminal kinase, and the translocation of nuclear factor-κB and p65 through Toll-interacting protein. Treatment with quercetin resulted in a significant decrease in prostaglandin E2 and cyclooxygenase-2 levels as well as inducible nitric oxide synthase-mediated nitric oxide production induced by lipopolysaccharide. Taken together, these findings represent new insights into the understanding of negative regulatory mechanisms of the TLR4 signaling pathway and effective therapeutic intervention for the treatment of inflammatory disease.


Ebola Virus Glycoprotein Induces an Innate Immune Response In vivo via TLR4
Ebola Virus Glycoprotein Induces an Innate Immune Response In vivo via TLR4 - PubMed
Pre-treatment of mice with a TLR4 antagonist inhibited GP-induced cytokine production and recruitment of immune cells to the DLN. EBOV GP also upregulated the expression of costimulatory molecules in bone marrow derived macrophages suggesting its ability to enhance APC stimulatory capacity, which is critical for the induction of effective antigen-specific adaptive immunity. Collectively, these results provide the first in vivo evidence that early innate immune responses to EBOV GP are mediated via the TLR4 pathway and are able to modulate the innate-adaptive interface.

Ageing potentiates diet-induced glucose intolerance, β-cell failure and tissue inflammation through TLR4.
Ageing potentiates diet-induced glucose intolerance, β-cell failure and tissue inflammation through TLR4 - PubMed
Ageing and obesity are two major risk factors for the development of type 2 diabetes (T2D). A chronic, low-grade, sterile inflammation contributes to insulin resistance and β-cell failure. Toll-like receptor-4 (TLR4) is a major pro-inflammatory pathway; its ligands as well as downstream signals are increased systemically in patients with T2D and at-risk individuals. In the present study we investigated the combined effects of high fat/high sucrose diet (HFD) feeding, ageing and TLR4-deficiency on tissue inflammation, insulin resistance and β-cell failure. In young mice, a short-term HFD resulted in a mildly impaired glucose tolerance and reduced insulin secretion, together with a β-cell mass compensation. In older mice, HFD further deteriorated insulin secretion and induced a significantly impaired glucose tolerance and augmented tissue inflammation in adipose, liver and pancreatic islets, all of which was attenuated by TLR4 deficiency. Our results show that ageing exacerbates HFD-induced impairment of glucose homeostasis and pancreatic β-cell function and survival, and deteriorates HFD-induced induction of mRNA expression of inflammatory cytokines and pro-inflammatory macrophage markers. TLR4-deficiency protects against these combined deleterious effects of a high fat diet and ageing through a reduced expression of inflammatory products in both insulin sensitive tissues and pancreatic islets.

Inhibition of TLR4 alleviates the inflammation and apoptosis of retinal ganglion cells in high glucose.
Inhibition of TLR4 alleviates the inflammation and apoptosis of retinal ganglion cells in high glucose - PubMed

TLR4-Induced Local Adipose Inflammation Critically Regulates Glucose Homeostasis
TLR4-Induced Local Adipose Inflammation Critically Regulates Glucose Homeostasis

Enhancement of LPS-Induced Microglial Inflammation Response via TLR4 Under High Glucose Conditions
Enhancement of LPS-Induced Microglial Inflammation Response via TLR4 Under High Glucose Conditions
Background: Microglia activation mediated by toll-like receptor 4 (TLR4) plays an important role in neuroinflammation and postoperative cognitive dysfunction (POCD). Diabetes mellitus (DM) has been recently suggested as an independent risk factor for POCD. In this study, we investigate the potential exacerbation of the inflammatory response in primary microglia due to high glucose conditions. Methods: Primary microglial cells were exposed to normal glucose (25 mmol/L) and high glucose (35 mmol/L) levels alone or with lipopolyscaccharide (LPS 0, 2, 5, 10 ng/mL). The pro-inflammatory response of the cells was assessed by measuring changes in cytokine levels and the evaluation of associated signaling pathways. Results: Neither high glucose nor low LPS (≤5ng/ml) alone had an effect on TNF-a and IL-6 levels, but the combination of low LPS and high glucose stimulated the inflammatory response. Analyses of the associated signaling pathways demonstrated that high glucose enhanced the LPS-induced microglial activation via the TLR4/JAK2/STAT3 pathway. Conclusion: This study demonstrates that high glucose, one of the key abnormalities characteristic of DM, can augment LPS-induced microglial activation and inflammatory cytokine levels through the TLR4/JAK2/STAT3 pathway, offering new insight into the pathophysiological relationship between DM and POCD.

Diabetes Exacerbates Infection via Hyperinflammation by Signaling through TLR4 and RAGE
https://mbio.asm.org/content/8/4/e00818-17
For more than a century, diabetic patients have been considered immunosuppressed due to defects in phagocytosis and microbial killing. We confirmed that diabetic mice were hypersusceptible to bacteremia caused by Gram-negative bacteria (GNB), dying at inocula nonlethal to nondiabetic mice. Contrary to the pervasive paradigm that diabetes impedes phagocytic function, the bacterial burden was no greater in diabetic mice despite excess mortality. However, diabetic mice did exhibit dramatically increased levels of proinflammatory cytokines in response to GNB infections, and immunosuppressing these cytokines with dexamethasone restored their resistance to infection, both of which are consistent with excess inflammation. Furthermore, disruption of the receptor for advanced glycation end products (RAGE), which is stimulated by heightened levels of AGEs in diabetic hosts, protected diabetic but not nondiabetic mice from GNB infection. Thus, rather than immunosuppression, diabetes drives lethal hyperinflammation in response to GNB by signaling through RAGE.
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Physicians and scientists have subscribed to the dogma that diabetes predisposes the host to worse outcomes from infections because it suppresses the immune system. This understanding was based largely on ex vivo studies of blood from patients and animals with diabetes. However, we have found that the opposite is true and worse outcomes from infection are caused by overstimulation of the immune system in response to bacteria. This overreaction occurs by simultaneous ligation of two host receptors: TLR4 and RAGE. Both signal via a common downstream messenger, MyD88, triggering hyperinflammation. In summary, contrary to hundred-year-old postulations about immune suppression in diabetic hosts, we find that diabetes instead predisposes to more severe infections because of additional inflammatory output through dual activation of MyD88 by not only TLR4 but also RAGE. It is the activation of RAGE during GNB infections in those with diabetes that accounts for their heightened susceptibility to infection compared to nondiabetic hosts.
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We have previously shown that A. baumannii infections result in profound hyperinflammation and sepsis in nondiabetic mice via TLR4 (25). We therefore sought to determine whether TLR4 disruption also mitigated mortality in diabetic mice. While all wild-type mice (C3H/Fe) with streptozotocin-induced diabetes died from A. baumannii infection, diabetic TLR4 mutant mice (C3H/He) had markedly improved survival (Fig. 3B). Similarly, a proprietary small-molecule competitive TLR4 antagonist (E5564, 10 mg/kg/day intravenously [i.v.] for 4 days postinfection) completely protected mice from otherwise lethal A. baumannii infection (Fig. 3C). Furthermore, knocking out TLR4 in C57BL/6 mice did not affect the hyperglycemia in DIO mice (Fig. 3D) but did completely protect them from lethal infection (Fig. 3E). These data confirm that diabetic mice are protected against A. baumannii infection in the absence of TLR4 signaling, as was previously found in nondiabetic mice.
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Despite worse survival, DIO diabetic mice did not have greater bacterial burdens or higher serum endotoxin levels than nondiabetic mice, whether wild type or TLR4 knockout (TLR4 KO) (Fig. 4A and B). Tellingly, DIO diabetic TLR4 KO mice had marked improvements in sepsis biomarkers and near-baseline (32–34) levels of inflammatory cytokines compared to DIO diabetic wild-type mice (Fig. 4C and D). These data further underscore the lack of correlation between outcomes of infection and innate immune clearance of bacteria, instead attributing mortality to hyperinflammation in diabetic hosts.
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The increased susceptibility of diabetic patients to acute bacterial infections—particularly those caused by Gram-negative bacteria—was noted in the 19th century (40). As early as 1907, the mechanism driving the increased severity of infections in diabetic patients was attributed to suppressed phagocytic clearance of microbes (15–18, 20–22, 41–43). Notwithstanding these conclusions, which were primarily drawn from in vitro and ex vivo assays of phagocyte function, we now report that diabetes causes the host to become hypersusceptible to infections caused by Gram-negative bacteria through immune paralysis, independent of bacterial density/clearance. Rather, the hypersusceptibility of diabetic hosts to Gram-negative bacterial infections is primarily due to hyperinflammation—not immunosuppression—inherent to the diabetic host.

TLR4 signaling occurs during infection for both diabetic and nondiabetic mice, but RAGE signaling increases susceptibility to infection exclusively in diabetic mice. By eliminating RAGE signaling in diabetic mice, their susceptibility to infection was reverted to the level of nondiabetic mice. TLR4 and RAGE signaling converge at MyD88, and hence, diabetic mice experience dual activation of MyD88 from two distinct receptors, whereas nondiabetic mice activate MyD88 through TLR4 alone. Our findings thus indicate that diabetic mice had increased mortality from infections caused by Gram-negative bacteria not because of immunosuppression but because of hyperinflammation driven by TLR4 and compounded by RAGE, both signaling through a common pathway via MyD88.
 
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rockarolla

rockarolla

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Can TLR4 over-stimulation leads to impaired acute bacteria clearance?

Can unresolved BB acute bacteria infection be a persistent trigger of TLR4 induced chronic inflammation?

Infection with the Lyme disease pathogen suppresses innate immunity in mice with diet‐induced obesity
Infection with the Lyme disease pathogen suppresses innate immunity in mice with diet‐induced obesity
Obesity is a major global public health concern. Immune responses implicated in obesity also control certain infections. We investigated the effects of high‐fat diet‐induced obesity (DIO) on infection with the Lyme disease bacterium Borrelia burgdorferi in mice. DIO was associated with systemic suppression of neutrophil‐ and macrophage‐based innate immune responses. These included bacterial uptake and cytokine production, and systemic, progressive impairment of bacterial clearance, and increased carditis severity. B. burgdorferi‐infected mice fed normal diet also gained weight at the same rate as uninfected mice fed high‐fat diet, toll‐like receptor 4 deficiency rescued bacterial clearance defects, which greater in female than male mice, and killing of an unrelated bacterium (Escherichia coli) by bone marrow‐derived macrophages from obese, B. burgdorferi‐infected mice was also affected. Importantly, innate immune suppression increased with infection duration and depended on cooperative and synergistic interactions between DIO and B. burgdorferi infection. Thus, obesity and B. burgdorferi infection cooperatively and progressively suppressed innate immunity in mice.
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Experiments were also performed comparing wild‐type C3H/HeN and toll‐like receptor 4 (TLR4)‐deficient C3H/HeJ male mice to determine whether TLR4 status affected B. burgdorferi infection in DIO. TLR4 is not required for immune responses to B. burgdorferi infection in vivo, but contributes to B. burgdorferi‐elicited cytokine secretion in macrophages, promotes the development of insulin‐resistant hyperglycemia in response to HFD, and is a key metabolic sensor of lipids

Figure 1:
PubMed Central, Figure 1: Cell Microbiol. 2017 May; 19(5): e12689. Published online 2016 Nov 25. doi: 10.1111/cmi.12689
Progressive, systemic, and toll‐like receptor (TLR)4‐dependent impairment of Borrelia burgdorferi clearance in diet‐induced obesity (DIO).

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Hyperglycemia induces Toll-like receptor-2 and -4 expression and activity in human microvascular retinal endothelial cells: implications for diabetic retinopathy.
Hyperglycemia induces Toll-like receptor-2 and -4 expression and activity in human microvascular retinal endothelial cells: implications for diabetic retinopathy - PubMed

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Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage.
Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage - PubMed
We recently found that ethanol can promote TLR4 signaling in glial cells by triggering the induction of inflammatory mediators and causing cell death, suggesting that the TLR4 response could be an important mechanism of ethanol-induced neuroinflammation.

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(PDF) Synergistic Inflammation Is Induced by Blood Degradation Products with Microbial Toll-Like Receptor Agonists and Is Blocked by Hemopexin
Detection of microbial components by immune cells via Toll-like receptors (TLRs) with subsequent induction of inflammation is essential for host defense. However, an overactive immune response can cause tissue damage and sepsis. The endogenous molecule hemoglobin and its derivative heme are often released into tissue compartments where there is infection in the presence of degrading blood. We found that hemoglobin synergizes with multiple TLR agonists to induce high levels of tumor necrosis factor and interleukin-6 from macrophages and that this synergy is independent of TLR4 and MyD88.

Pathways Involved in the Synergistic Activation of Macrophages by Lipoteichoic Acid and Hemoglobin
Pathways Involved in the Synergistic Activation of Macrophages by Lipoteichoic Acid and Hemoglobin
Lipoteichoic acid (LTA) is a Gram-positive cell surface molecule that is found in both a cell-bound form and cell-free form in the host during an infection. Hemoglobin (Hb) can synergize with LTA, a TLR2 ligand, to potently activate macrophage innate immune responses in a TLR2- and TLR4-dependent way. At low levels of LTA, the presence of Hb can result in a 200-fold increase in the secretion of IL-6 following macrophage activation. Six hours after activation, the macrophage genes that are most highly up-regulated by LTA plus Hb activation compared to LTA alone are cytokines, chemokines, receptors and interferon-regulated genes.

Hemoglobin, a newly recognized lipopolysaccharide (LPS)-binding protein that enhances LPS biological activity.
Hemoglobin, a newly recognized lipopolysaccharide (LPS)-binding protein that enhances LPS biological activity - PubMed

Hemoglobin increases mortality from bacterial endotoxin.
Hemoglobin increases mortality from bacterial endotoxin.
Cell-free hemoglobin (Hb) is being developed as an erythrocyte substitute. We have previously demonstrated that cell-free Hb is an endotoxin-binding protein which disaggregates endotoxin and subsequently increases the biological activity of endotoxin in several in vitro assays. Because much of the morbidity and mortality associated with gram-negative bacterial infection is the result of pathophysiologic responses to bacterial lipopolysaccharide (LPS; endotoxin), we studied the effect of Hb on LPS-mediated mortality. Hb infused intravenously into mice before, coincident with, or after intraperitoneal LPS injection substantially increased LPS-related mortality from <5% to 50 to 70% 24 h after administration of LPS and from 50% to 60 to 90% at 48 h. Enhanced mortality was observed over a range of doses of injected LPS. At a given LPS dose, enhancement of mortality was shown to be dependent on the dose of Hb administered. Unmodified native human Hb, alpha-alpha-cross-linked human Hb, and beta-beta-cross-linked human or bovine Hb all were shown to enhance LPS-mediated mortality. Depressed reticuloendothelial cell function may have contributed to the enhanced mortality from LPS in the presence of Hb. Therefore, Hb-based blood substitutes, which are currently undergoing clinical trials, may intensify the potentially fatal effects of the sepsis syndrome in patients with trauma, infection, or hypotension who receive Hb for erythrocyte replacement.
 
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rockarolla

rockarolla

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A lot of common anti inflammatory substances are detected of being guilty in inducing TLRs hyporesponsiveness. Just looking up what substances sick people are usually use to palliate inflammation symptoms:

Effects of Vitamin C or E on the Pro-inflammatory Cytokines, Heat Shock Protein 70 and Antioxidant Status in Broiler Chicks under Summer Conditions
However, the mRNA expression of interleukin (IL)-1β, IL-6, interferon (IFN)-γ, Toll like receptor (TLR)-4 and HSP70 in the liver of birds fed diet containing vitamin C significantly (p<0.05) decreased compared with those in birds fed basal diet. Dietary vitamin E also showed a significant (p<0.05) decrease in the mRNA expression of IL-6 and HSP70 compared with a basal diet. Total antioxidant status (TAS) in serum of birds fed vitamin C supplemented diet was significantly (p<0.05) higher with than that in birds a basal diet.

Dietary L-theanine alleviated lipopolysaccharide-induced immunological stress in yellow-feathered broilers
Dietary L-theanine alleviated lipopolysaccharide-induced immunological stress in yellow-feathered broilers
The results indicated that L-theanine had potential to alleviate LPS-induced immune stress in broilers.

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Glucocorticoids inhibit the innate immune system of human corneal fibroblast through their suppression of toll-like receptors
Glucocorticoids inhibit the innate immune system of human corneal fibroblast through their suppression of toll-like receptors
Incubation of HCFs with hydrocortisone(Cortef) markedly inhibited the expression of TLR2 and TLR4 mRNAs and decreased the release of IL-6 and IL-8 in a dose-dependent manner. Western blot analysis confirmed that expression of TLR2, TLR4, and pIκB-α was also downregulated in response to hydrocortisone. The result of ELISA also showed the release of IL-6 and IL-8 can also be inhibited by hydrocortisone. However, all these inhibitions were counteracted after pretreatment with anti-TLR2 and anti-TLR4 monoclonal antibodies.
 
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rockarolla

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Histamine promotes the expression of receptors TLR2 and TLR4 and amplifies sensitivity to lipopolysaccharide and lipoteichoic acid treatment in human gingival fibroblasts
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Histamine induces Toll-like receptor 2 and 4 expression in endothelial cells and enhances sensitivity to Gram-positive and Gram-negative bacterial cell wall components.
Histamine induces Toll-like receptor 2 and 4 expression in endothelial cells and enhances sensitivity to Gram-positive and Gram-negative bacterial cell wall components - PubMed

Common antihistamine drugs:

Azelastine eyedrops (Optivar), Azelastine nasal sprays (Astelin, Astepro), Carbinoxamine (Palgic), Cyproheptadine, Desloratadine (Clarinex), Emedastine eyedrops (Emadine), Hydroxyzine (Atarax, Vistaril), Levocabastine eyedrops (Livostin), Levocabastine oral (Xyzal), Brompheniramine (Dimetane), Cetirizine (Zyrtec), Chlorpheniramine (Chlor-Trimeton), Clemastine (Tavist), Diphenhydramine (Benadryl), Fexofenadine (Allegra), Loratadine (Alavert, Claritin)

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Dietary Omega-3 Fatty Acid Supplementation Reduces Inflammation in Obese Pregnant Women: A Randomized Double-Blind Controlled Clinical Trial
Dietary Omega-3 Fatty Acid Supplementation Reduces Inflammation in Obese Pregnant Women: A Randomized Double-Blind Controlled Clinical Trial

Study Design
A randomized, double-masked controlled trial was conducted in overweight/obese pregnant women that were randomly assigned to receive DHA plus EPA (2g/day) or the equivalent of a placebo twice a day from week 10–16 to term. Inflammatory pathways were characterized in: 1) adipose tissue and placenta of treated vs. untreated women; and 2) adipose and trophoblast cells cultured with long chain FAs.

Results
The sum of plasma DHA and EPA increased by 5.8 fold and ω-3 FA/ ω-6 FA ratio was 1.5 in treated vs. untreated women (p< 0.005). Plasma CRP concentrations were reduced (p<0.001). The adipose tissue and placenta of treated women exhibited a significant decrease in TLR4 adipose and placental expression as well as IL6, IL8, and TNFα In vitro, EPA and DHA suppressed the activation of TLR4, IL6, IL8 induced by palmitate in culture of adipose and trophoblast cells.

Conclusion
Supplementation of overweight/obese pregnant women with dietary ω-3 FAs for >25 weeks reduced inflammation in maternal adipose and the placental tissue. TLR4 appears as a central target of the anti-inflammatory effects at the cellular level.


Butyrate upregulates the TLR4 expression and the phosphorylation of MAPKs and NK-κB in colon cancer cell in vitro
Butyrate upregulates the TLR4 expression and the phosphorylation of MAPKs and NK-κB in colon cancer cell in vitro
Microbiota and its induced inflammation in colorectal mucosa have been considered risk factors for the development of colorectal carcinogenesis. Previous studies demonstrated that the coexisting elements of microbiota in the gut, such as short chain fatty acids (SCFAs) and lipopolysaccharides (LPS), which exhibited regulatory effects on the intestinal epithelial cells individually. Unfortunately, the association between butyrate and the toll-like receptor (TLR) signaling pathway in the development of colon cancer is not fully elucidated. In the present study, by culturing human colon cancer SW480 cells or mouse colon cancer CT26 cells with butyrate and/or TLR4 ligand LPS in vitro, it was identified that butyrate suppressed the growth and promoted apoptosis of these cancer cells. Notably, the expression levels of TLR4 and CD14 were markedly increased on these butyrate-treated cells, but not on LPS-alone treated cells. Additionally, butyrate treatment induced the phosphorylation of extracellular signal-regulated kinase, tumor protein 38, c-Jun NH2-terminal kinase and nuclear factor-κB (NF-κB) p65, and then promoted the pro-inflammatory cytokine tumor necrosis factor-α, but not interleukin 6 secretion in SW480 and CT26 cells. Therefore, butyrate treatment regulates the expression of TLR4, mitogen-activated protein kinase and NF-κB signal pathway activation and pro-inflammatory response in vitro. Although the exact mechanisms have not been fully explored, these results suggested that butyrate and LPS-TLR4 signaling mediated innate immunity in colon cancer cells through two distinct but inter-regulated pathways. Thus, butyrate can further initiate innate immunity against tumor cells by upregulating the TLR4 expression and activation to preserve intestinal homeostasis.

Metformin attenuates the TLR4 inflammatory pathway in skeletal muscle of diabetic rats.
Metformin attenuates the TLR4 inflammatory pathway in skeletal muscle of diabetic rats - PubMed
RESULTS:
Metformin treatment increased whole-body insulin sensitivity. This regulation was accompanied by a parallel change of p-AMPK and by an inverse regulation of TLR4 and NF-κB contents in the soleus muscle (r = 0.7229, r = -0.8344 and r = -0.7289, respectively, Pearson correlation; p < 0.05). Metformin treatment increased IκB content when compared to D rats. In addition, metformin treatment decreased p-JNK independently of TLR2 signal in diabetic rats.

CONCLUSION:
In summary, the results indicate a relationship between muscular TLR4, p-AMPK and NF-κB content and insulin sensitivity. The study also highlights that in situations of insulin resistance, such as in diabetic subjects, metformin treatment may prevent attenuation of activation of the inflammatory pathway.


TLR4 and Insulin Resistance
TLR4 and Insulin Resistance
Chronic inflammation is a key feature of insulin resistance and obesity. Toll-Like Receptor 4 (TLR4), involved in modulating innate immunity, is an important mediator of insulin resistance and its comorbidities. TLR4 contributes to the development of insulin resistance and inflammation through its activation by elevated exogenous ligands (e.g., dietary fatty acids and enteric lipopolysaccharide) and endogenous ligands (e.g., free fatty acids) which are elevated in obese states. TLR4, expressed in insulin target tissues, activates proinflammatory kinases JNK, IKK, and p38 that impair insulin signal transduction directly through inhibitory phosphorylation of insulin receptor substrate (IRS) on serine residues. TLR4 activation also leads to increased transcription of pro-inflammatory genes, resulting in elevation of cytokine, chemokine, reactive oxygen species, and eicosanoid levels that promote further insulin-desensitization within the target cell itself and in other cells via paracrine and systemic effects. Increased understanding of cell type-specific TLR4-mediated effects on insulin action present the opportunity and challenge of developing related therapeutic approaches for improving insulin sensitivity while preserving innate immunity.

Toll-Like Receptor 4 in Inflammation and Angiogenesis: A Double-Edged Sword
Toll-Like Receptor 4 in Inflammation and Angiogenesis: A Double-Edged Sword
Adenosine receptor signaling plays an important role in inflammation. Adenosine is produced by many different cell types and is elevated in conditions such as hypoxia, ischemic conditions, and stress. So far, four adenosine receptors have been reported, i.e., the A1, A2A, A3B, and A3 receptors (26). The synergistic effect of A2AR is not restricted to TLR4, but TLR2, 7, and 9 also lead to high VEGF production in the presence of adenosine signaling (22).

Adenosine reduces cell surface expression of toll-like receptor 4 and inflammation in response to lipopolysaccharide and matrix products.
Adenosine reduces cell surface expression of toll-like receptor 4 and inflammation in response to lipopolysaccharide and matrix products - PubMed
Recent evidence suggests that Toll-like receptor 4 (TLR4) is not only involved in innate immunity but is also an important mediator of adverse left ventricular remodeling and heart failure following acute myocardial infarction (MI). TLR4 is activated by lipopolysaccharide (LPS) but also by products of matrix degradation such as hyaluronic acid and heparan sulfate. Although cardioprotective properties of adenosine (Ado) have been extensively studied, its potential to interfere with TLR4 activation is unknown. We observed that TLR4 pathway is activated in white blood cells from MI patients. TLR4 mRNA expression correlated with troponin T levels (R (2) = 0.75; P = 0.01) but not with levels of white blood cells and C-reactive protein. Ado downregulated TLR4 expression at the surface of human macrophages (-50%, P < 0.05). Tumor necrosis factor-α production induced by the TLR4 ligands LPS, hyaluronic acid, and heparan sulfate was potently inhibited by Ado (-75% for LPS, P < 0.005). This effect was reproduced by the A2A Ado receptor agonist CGS21680 and the non-selective agonist NECA and was inhibited by the A2A antagonist SCH58261 and the A2A/A2B antagonist ZM241,385. In contrast, Ado induced a 3-fold increase of TLR4 mRNA expression (P = 0.008), revealing the existence of a feedback mechanism to compensate for the loss of TLR4 expression at the cell surface. In conclusion, the TLR4 pathway is activated after MI and correlates with infarct severity but not with the extent of inflammation. Reduction of TLR4 expression by Ado may therefore represent an important strategy to limit remodeling post-MI.

Is There a Relation between Adenosine and Caffeines’ Mechanisms of Action and Toll-Like Receptor-4 (TLR-4)?
Is There a Relation between Adenosine and Caffeines’ Mechanisms of Action and Toll-Like Receptor-4 (TLR-4)?
Previous studies showed that endogenous adenosine, an anti-inflammatory agent, was released at sites of injury and inflammation thereby decreasing the excessive production of pro-inflammatory cytokines. Caffeine, a non-specific adenosine blocker, has been reported in several studies to have opposing immune-modulatory effects. In this study, the effects of caffeine and adenosine on TLR-4 in promoting or decreasing the production of TNF-α and IL-12 by LPS-stimulated monocytes were investigated. Monocytes were isolated using Pluribead® kit from pooled blood obtained from ten volunteers. The monocytes were then incubated for 24 hours with Lipopolysaccharide (pLPS) extracted from Escherichia coli (aTLR-4 ligand activator), adenosine, caffeine and LPS extracted from Rhodobacter sphaeroides (LPS-RS, a TLR-4 ligand blocker), each alone or in different combinations. Later, the levels of pro-inflammatory cytokines TNFα and IL-12 were assessed in supernatants using an Enzyme Linked Immuno Assay (ELISA). Caffeine and adenosine significantly reduced the amount of TNFα and IL-12 produced by LPS-stimulated monocytes. Regarding non-stimulated and LPS-RS blocked monocytes, the presence of adenosine and caffeine significantly decreased TNFα levels produced by these cells but had little or non-significant effect on the levels of IL-12. In conclusion, both caffeine and adenosine blocked the production of the pro-inflammatory cytokines by pLPS-stimulated-monocytes. TLR-4 did not appear to be involved in the signaling pathway of caffeine and adenosine since blocking of TLR-4 did not abolish the effects of adenosine and caffeine on production of cytokines, in particular TNF-α.
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3.4. Effect of Caffeine on TLR-4

When caffeine was added to non-stimulated monocytes or LPS-RS blocked monocytes, it resulted in a significant decrease in the levels of TNF-α by twenty nine fold and fifty fold respectively (p = 0.0001, and p = 0.0001 respectively) but IL-12 levels were not affected significantly (p > 0.05). Moreover, it is worth noting that in all scenarios caffeine was decreasing TNF-α levels more than adenosine.
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It is worth noting that the combination of adenosine and caffeine decreased TNF-α levels more than when each reagent was used alone.

Adenosine is required for sustained inflammasome activation via the A2A receptor and the HIF-1α pathway
Adenosine is required for sustained inflammasome activation via the A2A receptor and the HIF-1α pathway - Nature Communications

A2B adenosine receptors protect against sepsis-induced mortality by dampening excessive inflammation
https://www.ncbi.nlm.nih.gov/pubmed/20505145
 
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Interaction between Cannabinoid System and Toll-Like Receptors Controls Inflammation
Interaction between Cannabinoid System and Toll-Like Receptors Controls Inflammation

Impact of Cannabinoids on Toll-Like Receptor Responses

Because all immune cells examined so far express cannabinoid receptors regardless of their cell lineage, all types of immunity are sensitive to cannabinoid modulation [10–12]. The importance of the cannabinoid system in regulating immune competency is revealed by altered immune status in mice genetically deficient in cannabinoid receptors [15]. In terms of adaptive immunity, cannabinoids usually suppress primary antibody responses to T cell-dependent antigens, induction of cytotoxic CD8+ T cells, and cytokine production by helper CD4+ T cells, whereas other adaptive immune responses are unaffected or enhanced [10–12]. The current view is that cannabinoid exposure skews T cell responses leading to suppression of cell-mediated immunity and inflammatory reactions [10–12]. Furthermore, cannabinoids impact innate immunity that mediates inflammatory responses and promotes initiation of adaptive immune responses. For example, alveolar macrophages isolated from chronic marijuana users have compromised phagocytosis of microorganisms, ability to kill bacteria, and production of proinflammatory cytokines [16, 17]. These consequences of drug use parallel in vitro cannabinoid suppression of immune functions by monocytes, macrophages, and macrophage cell lines of human and rodent origins [10–12]. My laboratory reported that cannabinoids impair the ability of murine macrophages to function as antigen-presenting cells resulting in depressed helper CD4+ T cell responses [18–20]. Furthermore, macrophages from mice lacking cannabinoid receptor expression are refractory to cannabinoid suppression of antigen-presenting cell function [21, 22]. Therefore, cannabinoids can exert their influence on an immune response before helper CD4+ T cell activation.
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Cannabinoid studies regarding TLRs have concentrated on bacterial LPS responses via TLR4 as a classic model for inflammation (Table 1). For the most part, exogenous and endogenous cannabinoids interfere with proinflammatory cytokine and nitric oxide production by LPS- or LPS/interferon-γ-stimulated monocytes, macrophages, microglia, and macrophage cell lines in culture [10–12, 92, 93]. However, one study reported increased interleukin-1β secretion by LPS-activated resident peritoneal cells caused by Δ9-tetrahydrocannabinol [94] in opposition to other investigations [95, 96]. Cannabinoids display biphasic dose-response curves for cytokine secretion in some culture systems [96, 97], which may account for this apparent discrepancy. Interestingly, Δ9-tetrahydrocannabinol decreases LPS-induced cyclooxygenase-2 expression in mouse macrophage J774 cell line [93], which would diminish endocannabinoid 2-arachidonoyl-glycerol metabolism, thereby augmenting immune suppression. In addition, chronic marijuana use increases CB1 and CB2 receptor expression on peripheral blood monocytes [98], which may enhance cannabinoid sensitivity. Thus, exogenous cannabinoids may alter the endocannabinoid system leading to greater suppression of the LPS response.
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LPS administration in animals is frequently used as in vivo models of inflammation and bacterial sepsis (Table 2). A synthetic cannabinoid diminishes LPS-stimulated proinflammatory cytokine levels in the brain and blood of rats [112]. In the LPS-induced pulmonary inflammation model, exogenous and endogenous cannabinoids dose-dependently decrease tumor necrosis factor-α level in bronchoalveolar fluid and reduce neutrophil infiltration into the lungs in mice [113]. Synthetic cannabinoids rescue C. parvum-primed mice from LPS lethality and diminish serum proinflammatory cytokine levels [114]. Likewise, a nonpsychoactive synthetic cannabinoid abolishes LPS-induced hypotensive response in rats and rescues mice from the lethal effects of LPS and D-galactosamine coadministration [115]. A CB2 receptor-selective agonist also protects against mortality and acute liver failure, decreases proinflammatory cytokines levels, and increases inhibitory interleukin-10 level in mice given LPS and D-galactosamine  [116]. Upon in vitro LPS stimulation, cytokine and nitric oxide production by macrophages from mice previously given Δ9-tetrahydrocannabinol remain suppressed without additional drug in the cultures [102]. Perhaps, cannabinoid immune suppression induced in vivo may persist after drug removal. Therefore, the effects of cannabinoids on LPS activation in several animal models, in general, parallel the in vitro finding
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Cannabinoid effects on in vitro TLR responses:
PubMed Central, Table 1: Mediators Inflamm. 2016; 2016: 5831315. Published online 2016 Aug 11. doi: 10.1155/2016/5831315
 
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Another very popular "detox"/LPS response feedback inhibitor: Vitamin C

Vitamin C alleviates LPS-induced cognitive impairment in mice by suppressing neuroinflammation and oxidative stress.

Zhang XY1, Xu ZP1, Wang W2, Cao JB1, Fu Q1, Zhao WX1, Li Y1, Huo XL1, Zhang LM3, Li YF3, Mi WD4.
Neuroinflammation is believed to be one of the primary causes of cognitive impairment. Previous studies showed that the antioxidant vitamin C (Vit C) performs many beneficial functions such as immunostimulant and anti-inflammatory actions, but its role in inflammatory cognitive impairment is unclear. In the current study, we investigated the effect and possible mechanism of action of Vit C in lipopolysaccharide (LPS)-induced cognitive impairment. Intracerebroventricular LPS-induced memory impairment was used as the model for neuroinflammatory cognitive dysfunction. Vit C was administered by intracerebroventricular microinjection 30 min prior to LPS exposure. It was found that Vit C significantly protected animals from LPS-induced memory impairment as evidenced by improved performance in the Morris water maze and novel object recognition tests without changes in spontaneous locomotor activity. Vit C pretreatment inhibited the activation of microglia and the production of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Furthermore, Vit C pretreatment markedly decreased the malondialdehyde (MDA) level, increased superoxide dismutase (SOD) activity, and modulated the Bax/Bcl-2 ratio and p-p38 MAPK activation in the hippocampus of LPS-treated mice. Together, these results suggest that vitamin C pretreatment could protect mice from LPS-induced cognitive impairment, possibly through the modulation of oxidative stress and inflammatory responses.
 
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Some TLR4 agonists(aka toxins):


Optimizing the utilization of aluminum adjuvants in vaccines: you might just get what you want
Optimizing the utilization of aluminum adjuvants in vaccines: you might just get what you want - npj Vaccines
The combination of immunostimulatory molecules that target different mechanisms to activate the immune response and aluminum can have synergistic effects that may result in a more effective or longer lasting immune response, and allow for a smaller amount of antigen in the vaccine (dose sparing). Aluminum adjuvants induce only weak Th1 and Th17 responses, which may be necessary for the induction of protective immunity against certain infectious diseases, such as malaria and tuberculosis. Adsorption of immunostimulatory molecules to aluminum adjuvants limits the systemic distribution of the molecules, which reduces the risk of systemic side-effects, and enhances the targeting of such molecules and co-adsorbed antigens to antigen-presenting cells recruited to the injection site.129,130 Ligands for pattern recognition receptors, in particular the Toll-like receptors (TLRs), are excellent candidates for combination adjuvants (Table 2) as they are localized at the cell membrane or in endosomal compartments and signal via MyD88 and TRIF pathways, that are complementary to aluminum adjuvant-activated cell signaling pathways. The AS04 adjuvant, comprised of aluminum adjuvants with the TLR4 agonist monophosphoryl lipid A, was the first combination adjuvant to be approved for use in licensed vaccines against human papilloma virus and hepatitis B.131

AS04, an aluminum salt- and TLR4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity.
AS04, an aluminum salt- and TLR4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity - PubMed

Adjuvant System 04 (AS04) combines the TLR4 agonist MPL (3-O-desacyl-4'-monophosphoryl lipid A) and aluminum salt. It is a new generation TLR-based adjuvant licensed for use in human vaccines. One of these vaccines, the human papillomavirus (HPV) vaccine Cervarix, is used in this study to elucidate the mechanism of action of AS04 in human cells and in mice. The adjuvant activity of AS04 was found to be strictly dependent on AS04 and the HPV Ags being injected at the same i.m. site within 24 h of each other. During this period, AS04 transiently induced local NF-kappaB activity and cytokine production. This led to an increased number of activated Ag-loaded dendritic cells and monocytes in the lymph node draining the injection site, which further increased the activation of Ag-specific T cells. AS04 was also found to directly stimulate those APCs in vitro but not directly stimulate CD4(+) T or B lymphocytes. These AS04-induced innate responses were primarily due to MPL. Aluminum salt appeared not to synergize with or inhibit MPL, but rather it prolonged the cytokine responses to MPL at the injection site. Altogether these results support a model in which the addition of MPL to aluminum salt enhances the vaccine response by rapidly triggering a local cytokine response leading to an optimal activation of APCs. The transient and confined nature of these responses provides further supporting evidence for the favorable safety profile of AS04 adjuvanted vaccines.

Inorganic mercury exposure in prairie voles (Microtus ochrogaster) alters the expression of toll-like receptor 4 and activates inflammatory pathways in the liver in a sex-specific manner.
Inorganic mercury exposure in prairie voles (Microtus ochrogaster) alters the expression of toll-like receptor 4 and activates inflammatory pathways in the liver in a sex-specific manner - PubMed
Environmental exposure to mercury can cause a number of adverse effects in humans including the disruption of endocrine function that may result in sex-specific effects. The present study was designed to characterize sex-specific effects of chronic inorganic mercury exposure on toll-like receptor (TLR) 2 and TLR4 and inflammatory signaling in the liver of prairie voles (Microtus ochrogaster). Following 10 weeks of exposure to mercury via drinking water, effects on protein expression levels of TLR2 and TLR4 and the downstream p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-kappa (NF-κB) signaling pathways were assessed. Using immunoblot analysis, we found that mercury exposure significantly enhanced the expression of TLR4 and activated p38 MAPK and NF-κB pathways in vole livers. This is the first report indicating that TLR4 may serve as a sensor for chronic mercury exposure in the liver.

Rational Design of a New Class of Toll-Like Receptor 4 (TLR4) Tryptamine Related Agonists by Means of the Structure- and Ligand-Based Virtual Screening for Vaccine Adjuvant Discovery
Rational Design of a New Class of Toll-Like Receptor 4 (TLR4) Tryptamine Related Agonists by Means of the Structure- and Ligand-Based Virtual Screening for Vaccine Adjuvant Discovery

Regulation of TLR4 in silica-induced inflammation: An underlying mechanism of silicosis.
Regulation of TLR4 in silica-induced inflammation: An underlying mechanism of silicosis - PubMed
Silicosis is an incurable lung disease affecting millions of workers in hazardous occupations. It is caused by chronic exposure to the dust that contains free crystalline silica. Silica-induced lung damage occurs by several main mechanisms including cell death by apoptosis, fibrosis and production of cytokines. However, the signal pathways involved in these mechanisms are not fully characterized. In this study, the toll-like receptor 4 (TLR4)-related signal pathway was examined in silica-treated U937-differentiated macrophages. The expression level of TLR4 was measured by both quantitative PCR and Western blot. Confirmation of the involvement of MyD88/TIRAP and NFκB p65 cascade was performed by Western blot. The secretion of cytokines IL-1β, IL-6, IL-10 and TNFα was measured by enzyme-linked immunosorbent assay. Our results showed that TLR4 and related MyD88/TIRAP pathway was associated with silica-exposure in U937-differentiated macrophages. Protein expression of TLR4, MyD88 and TIRAP was upregulated when the U937-differentiated macrophages were exposed to silica. However, the upregulation was attenuated when TLR4 inhibitor, TAK-242 was present. At different incubation times of silica exposure, it was found that NFκB p65 cascade was activated at 10-60 minutes. Release of cytokines IL-1β, IL-6, IL-10 and TNFα was induced by silica exposure and the induction of IL-1β, IL-6 and TNFα was suppressed by the addition of TAK-242. In conclusion, our study demonstrated that TLR4 and related MyD88/TIRAP pathway was involved in silica-induced inflammation in U937-differentiated macrophages. Downstream NFκB p65 cascade was activated within 1 hour when the U937-differentiated macrophages were exposed to silica. The better understanding of early stage of silica-induced inflammatory process may help to develop earlier diagnosis of silicosis.

[Involvement of Toll-like receptor in silica-induced tumor necrosis factor alpha release from human macrophage cell line].
[Involvement of Toll-like receptor in silica-induced tumor necrosis factor alpha release from human macrophage cell line] - PubMed
CONCLUSION:
TLR4 mediates silica-induced TNFalpha release from macrophages.
 
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So called 'antidepressants' are actually TLR4 antagonists:

Paroxetine(Paxil, Pexeva) differentially modulates LPS-induced TNFα and IL-6 production in mouse macrophages
Paroxetine differentially modulates LPS-induced TNFα and IL-6 production in mouse macrophages
Paroxetine is a selective serotonin reuptake inhibitor (SSRI) that is clinically used for the treatment of depression in human patients. Because of recent reports on the role of serotonin in modulating inflammation and the link between inflammation and depression, we sought to test the effect of paroxetine directly on macrophage response to an inflammatory stimulus. Lipopolysaccharide (LPS) treatment of mouse macrophages significantly enhanced TNFα and IL-6 production. Paroxetine treatment of macrophages however, significantly inhibited LPS-induced IL-6 production. In contrast, paroxetine enhanced LPS-induced TNFα production in macrophages. These effects of paroxetine were mimicked by fluoxetine, another SSRI. To determine if the effects of paroxetine are mediated via modulation of the 5-HT system, we treated macrophages with 5-HT or 5-HT receptor antagonist (LY215840) in the presence of LPS and/or paroxetine. 5-HT treatment by itself did not affect LPS-induced cytokine production. LY215840 however, reversed paroxetine's effect on LPS-induced TNFα production but not IL-6. To understand the signaling mechanisms, we examined paroxetine's effect on MAPK and NFκB pathways. While paroxetine inhibited LPS-induced IκBα phosphorylation, MAPK pathways were mostly unaffected. Together these data demonstrate that paroxetine has critical but differential effects on IL-6 and TNFα production in macrophages and that it likely regulates these cytokines via distinct mechanisms.

ROLE OF PAROXETINE IN INFLAMMATORY CYTOKINE RESPONSES IN MACROPHAGES
[PDF] ROLE OF PAROXETINE IN INFLAMMATORY CYTOKINE RESPONSES IN MACROPHAGES | Semantic Scholar
G-protein coupled receptors (GPCR) play a critical role in immunity by regulating the function of immune cells including macrophages. Along with their role in GPCR desensitization, G-protein receptor kinases (GRKs) exhibit GPCR-independent roles in modulating various intracellular signaling pathways that regulate inflammatory responses. Paroxetine, a FDA approved selective serotonin (5HT) re-uptake inhibitor (SSRI) used as an anti-depressant, selectively inhibits GRK2 in cardiomyocytes. We hypothesized that paroxetine inhibits GRK2 activity and affects LPS-induced inflammatory cytokine production in macrophages. Our results revealed that paroxetine decreases LPS-induced IL-6, IL-1β and increases TNFα levels in macrophages. To further evaluate if paroxetine mediated inflammatory cytokine response is through its ability to inhibit GRK2, RNA interference studies were performed with GRK2 siRNA smartpool. These experiments demonstrated that the effects of paroxetine on macrophages are GRK2-independent. Another SSRI, fluoxetine was also found to exert similar LPS-induced differential regulation of cytokine responses in macrophages. However, exogenous 5HT did not affect the inflammatory cytokine response in LPS-induced macrophages. Furthermore, paroxetine did not appear to modulate the following inflammatory signaling kinases in macrophages: pIκBα, pp105, pP38, pJNK1/2, and pERK1/2. A logical continuation of this study would be attempts to elucidate the intracellular pathways involved in SSRI-mediated molecular mechanisms that govern inflammatory cytokine response in macrophages.

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Differential effects of sertraline(zoloft) in a predator exposure animal model of post-traumatic stress disorder
Differential effects of sertraline in a predator exposure animal model of post-traumatic stress disorder
Pro- and Anti-Inflammatory Marker Protein. The PFC and hippocampus demonstrated elevated protein levels of IL-1β (A and B) and TLR4 (C and D) in the PTSD group. Conversely, the levels of AIC protein in these regions were lower for IL-4 (E and F) and IL-10 (G and H). Sertraline[Zoloft] administration also normalized the aberrant protein to levels similar as the control + Veh group.
PubMed Central, Figure 5: Front Behav Neurosci. 2014; 8: 256. Published online 2014 Jul 30. Prepublished online 2014 Jul 6. doi: 10.3389/fnbeh.2014.00256

Toll-Like Receptors in the Depressed and Suicide Brain
Toll-Like Receptors in the Depressed and Suicide Brain
...the protein expression of TLR3 and TLR4 was significantly increased in depressed suicide victims, but not in depressed non-suicide subjects compared with controls. The observed abnormalities of proinflammatory cytokines in the brain of suicide victims may be related to an abnormality of TLR3 and TLR4 over-expression. To our knowledge, this is the first study of TLRs in the brain of psychiatric subjects.

Prophylactic TLR9 stimulation reduces brain metastasis through microglia activation.
Prophylactic TLR9 stimulation reduces brain metastasis through microglia activation - PubMed
 
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Melatonin to cool down our bodies in sleep preparation:

Melatonin Suppresses Toll Like Receptor 4-Dependent Caspase-3 Signaling Activation Coupled with Reduced Production of Proinflammatory Mediators in Hypoxic Microglia
Melatonin Suppresses Toll Like Receptor 4-Dependent Caspase-3 Signaling Activation Coupled with Reduced Production of Proinflammatory Mediators in Hypoxic Microglia
Interestingly, melatonin treatment significantly suppressed caspase-3 activation. More importantly, melatonin also inhibited the increase in TLR4 protein and mRNA expression in hypoxic microglia.

melatonin-profile.jpg


Melatonin Inhibits Lipopolysaccharide-Induced Inflammation and Oxidative Stress in Cultured Mouse Mammary Tissue
Melatonin Inhibits Lipopolysaccharide-Induced Inflammation and Oxidative Stress in Cultured Mouse Mammary Tissue
 
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Plant Phenolic Compounds as Immunomodulatory Agents
Plant Phenolic Compounds as Immunomodulatory Agents
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Similar modes of action were established for daidzein (isoflavone (*)) [37], silibinin (flavonolignan) [38], fisetin (flavonol) [39], apigenin [36], and baicalin (flavone glycoside) [40] in LPS-stimulated DCs, all compounds exhibiting immunosuppressive activity by inhibiting cell maturation and activation. They significantly and dose-dependently inhibit the expression levels of maturation-associated cell surface markers including CD40, costimulatory molecules (CD80, CD86), and major histocompatibility complex class II (I-A(b)) molecule. An impaired induction of the T helper type 1 immune response and a normal cell-mediated immune response induced by the abovementioned compounds were noticed as it was previously found in the case of curcumin [41]. This well-known phytophenol is also a potential therapeutic adjuvant for DC-related acute and chronic diseases being highly efficient at Ag capture, via mannose receptor-mediated endocytosis [41]. The suppressive effect on DCs was also showed for another phenolic compound belonging to ellagitannins class, oenothein B; it was associated with the induction of apoptosis without the activation of caspase-3/7, 8, and 9; and this was supported by the morphological features indicating significant nuclear condensation [42].

Impact of polyphenols in phagocyte functions
Impact of polyphenols in phagocyte functions

Several studies support the hypothesis that polyphenols might regulate immune responses by suppressing toll-like receptor signaling. Epigallocatechin gallate-3, a polyphenol found in green tea, was shown to reduce in vitro TLR4 expression, after treatment with lipopolysaccharide, on the surface of murine macrophages and bone marrow dendritic cells.10,11 In addition, Byun et al (2012) showed that the 67 laminin receptor protein (67LR) acts as a cell surface receptor for gallate-3 epigallocatechin, playing a vital role in mediating inflammation by positively regulating the expression of toll-interacting protein (Tollip), a regulator of TLR4 signaling through 67LR. Green tea polyphenols may also decrease in vitro TLR4 protein expression levels in LPS-activated melanoma murine cells, inhibiting proliferation, migration, and invasion of melanoma cells.
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Trans-3,5,4-trihydroxystilbene (resveratrol), a polyphenol found in red grapes and other plant sources, has potent anti-inflammatory properties through negatively controlling in vitro microglial inflammation triggered by LPS stimulation.13 A study with microglial BV2-cells showed that resveratrol interfered in the oligomerization of TLR4 and, consequently, downregulated signaling cascades triggered by NF-kB and members of the signal transducer and activator of transcription (STAT) protein family, which are involved in pro-inflammatory mediator production.

(*):

Isoflavone content of selected foods(milligrams per 100 grams)
Isoflavone content of selected foods - Harvard Health

Analysis of Isoflavones in Foods:
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Gallic acid inhibits inflammatory response of RAW264.7 macrophages by blocking the activation of TLR4/NF-κB induced by LPS
[Gallic acid inhibits inflammatory response of RAW264.7 macrophages by blocking the activation of TLR4/NF-κB induced by LPS] - PubMed
Results: The expression levels of TNF-α, IL-1 and IL-6 were up-regulated in the RAW264.7 macrophages after stimulated by LPS. Gallic acid could reduce the elevated expression levels of TNF-α, IL-1 and IL-6 induced by LPS. The expression of TLR4 significantly increased after stimulated by LPS and NF-κB was activated. Gallic acid could reverse the above changes and prevent the activation of NF-κB. Conclusion Gallic acid could inhibit LPS-induced inflammatory response in RAW264.7 macrophages via TLR4/NF-κB pathway.

->

The Anti-Inflammatory and Antioxidant Potential of Pistachios (Pistacia vera L.) In Vitro and In Vivo
Flavonoids and phenolic acids in NP(natural raw shelled pistachios) and RP(roasted salted pistachios):

Gallic acid, Protocatechuic acid, Chlorogenic acid, Catechin, Epicatechin, Eriodictyol-7-O-glucoside, Quercetin-3-O-rutinoside, Isoquercetin, Daidzein, Eriodictyol, Luteolin.

Several reports have demonstrated the effectiveness of pistachio against oxidative stress and inflammation. In this study, we investigate if polyphenols extracts from natural raw shelled pistachios (NP) or roasted salted pistachio (RP) kernels have anti-inflammatory and antioxidant properties at lower doses than reported previously, in both in vitro and in vivo models. The monocyte/macrophage cell line J774 was used to assess the extent of protection by NP and RP pistachios against lipopolysaccharide (LPS)-induced inflammation. Moreover, antioxidant activity of NP and RP was assessed in an in vivo model of paw edema in rats induced by carrageenan (CAR) injection in the paw. Results from the in vitro study demonstrated that pre-treatment with NP (0.01, 0.1 and 0.5 mg/mL) and RP (0.01 and 0.1 mg/mL) exerted a significant protection against LPS induced inflammation. Western blot analysis showed NP reduced the degradation of IκB-α, although not significantly, whereas both NP and RP decreased the TNF-α and IL-1β production in a dose-dependent way. A significant reduction of CAR-induced histological paw damage, neutrophil infiltration and nitrotyrosine formation was observed in the rats treated with NP. These data demonstrated that, at lower doses, polyphenols present in pistachios possess antioxidant and anti-inflammatory properties.

Further, we stimulated cells with LPS to induce inflammatory response, and pre-treated cells with NP and RP. The results obtained showed a significant protective effect against LPS induced inflammatory process in cells pre-treated with NP at the three concentrations used (0.5 mg/mL, 0.1 mg/mL and 0.01 mg/mL), whereas pre-treatment with RP exerted significant protection only at the concentrations of 0.01 mg/mL and 0.1 mg/mL.

The COX-2 levels were significantly increased after LPS stimulation, whereas pre-treatment with both NP and RP at all concentrations tested significantly reduced COX-2 levels (Figure 4b).

Moreover, we investigated the levels of nitrite released into the culture medium by Griess reagent. The untreated control group released low levels of NO2−, whereas LPS stimulation significantly increased the levels of NO2− production (Figure 4c). Pre-treatment with both NP and RP extracts decreased NO production in a concentration-dependent manner (Figure 4c).

In the literature, there are several studies regarding the beneficial effects of pistachio. In particular, there are studies on carrageenan or LPS-induced acute inflammatory response [4,16], inflammatory bowel disease and colitis [21,35,36,37], cancer [38,39,40], allergic inflammation in asthmatic model [41] and many other experimental models. Furthermore, the antimicrobial properties of polyphenolic fractions obtained from natural raw and roasted salted pistachios have also been evaluated [42,43]. Several studies have reported the potent antioxidant, anti-inflammatory and anti-apoptotic potential of pistachio [44,45,46,47,48].
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Furthermore, it has been shown that the hydrophilic extract from Sicilian Pistacia L. is capable of influencing redox-sensitive signal transduction pathways thus modulating NF-κB activity and finally decreasing the regulation of iNOS expression, COX-2 and TNF-α [16,20,44,45].
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Therefore, we sought to evaluate where NP and RP polyphenols-rich extracts had effects on the expression of these proteins, even at lower doses than reported previously. Treatment with NP and RP significantly reduced TNF-α and IL-1β levels, and attenuated the production of iNOS. These observations are in agreement with previous studies evaluating the anti-inflammatory properties of plant materials and molecules of bioactives [51,52,53,54]. Thus, the antioxidant and anti-inflammatory properties of polyphenols from pistachios could be attributed to the reduction of the nitrosative stress and subsequent formation of NO. This was reported earlier, but at doses much higher than those used in the present study.

Taken together, our data demonstrated that polyphenols from pistachios, at lower doses that reported in literature, were able to protect from oxidative stress reducing the expression of markers of nitrosative stress such as iNOS, COX2 and NO formation.

Database on Polyphenol Content in Foods - Phenol-Explorer :: Phenol-Explorer is the first comprehensive database on polyphenol content in foods.

Ex: Gallic acid foods
Showing all foods in which the polyphenol Gallic acid is found - Phenol-Explorer
 
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Toll-Like Receptor Stimulation Enhances Phagocytosis and Intracellular Killing of Nonencapsulated and Encapsulated Streptococcus pneumoniae by Murine Microglia
https://iai.asm.org/content/78/2/865

Toll-like receptors (TLRs) are crucial pattern recognition receptors in innate immunity that are expressed in microglia, the resident macrophages of the brain. TLR2, -4, and -9 are important in the responses against Streptococcus pneumoniae, the most common agent causing bacterial meningitis beyond the neonatal period. Murine microglial cultures were stimulated with agonists for TLR1/2 (Pam3CSK4), TLR4 (lipopolysaccharide), and TLR9 (CpG oligodeoxynucleotide) for 24 h and then exposed to either the encapsulated D39 (serotype 2) or the nonencapsulated R6 strain of S. pneumoniae. After stimulation, the levels of interleukin-6 and CCL5 (RANTES [regulated upon activation normal T-cell expressed and secreted]) were increased, confirming microglial activation.

The TLR1/2, -4, and -9 agonist-stimulated microglia ingested significantly more bacteria than unstimulated cells (P < 0.05).

The presence of cytochalasin D[blocks the tyrosine phosphorylation of MD-2 in cells stimulated with LPS], an inhibitor of actin polymerizaton, blocked >90% of phagocytosis.

Along with an increased phagocytic activity, the intracellular bacterial killing was also increased in TLR-stimulated cells compared to unstimulated cells.

Together, our data suggest that microglial stimulation by these TLRs may increase the resistance of the brain against pneumococcal infections.
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Upon TLR stimulation, reactive microglia develop a phagocytic phenotype to engulf and kill microbes. In contrast to cytokine and chemokine induction, the phagocytic and bactericidal profiles of activated microglia have been explored less thoroughly. Our group has recently reported that TLR1/2, -4, and -9 agonists can increase the ability of murine microglial cells to phagocytose and kill intracellularly located Escherichia coli strains (36). The present data demonstrate that microglia can also phagocytose and kill Gram-positive bacteria which have a thicker cell wall and that stimulation of TLRs can increase their phagocytic and bactericidal activity. This applies for both nonencapsulated apathogenic and encapsulated pathogenic pneumococci. Stimulation with either a TLR1/2, -4, or -9 agonist significantly increased the ability of microglia to phagocytose pneumococci. From our data, the effect of the stimulation through the TLR9 system was clearly greater than the effect caused via TLR1/2 or TLR4. Similarly, phagocytosis and killing of live S. pneumoniae were found to be impaired in alveolar and bone marrow-derived macrophages from TLR9-deficient mice (1) and in blood-derived polymorphonuclear leukocytes from TLR2-deficient mice (23).
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An intact TLR signaling through the pathway organized by MyD88 appears to be necessary to protect the brain tissue against invading microorganisms. A poor outcome because of high bacterial counts in the CNS and severe bacteremia was observed in MyD88-deficient mice after intracisternal induction of pneumococcal meningitis (19). Similarly, MyD88−/− mice showed an increased susceptibility to pneumococcal colonization within the upper respiratory tract, an enhanced bacterial proliferation in infected lung tissue, precocious bacterial spread into the bloodstream, and increased mortality (2). These findings illustrate the importance of an intact innate immune system to efficiently limit the spread of S. pneumoniae.
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Stimulation of the TLR system is a potential target for the development of new therapies in multiple diseases (45). Several TLR agonists are currently at different stages of clinical trials (4). The TLR7 agonist imiquimod has been successfully used and approved for the treatment of warts associated with human papillomavirus and is in a second phase trial as a therapeutic agent for herpes simplex virus (HSV) infections (43). The TLR7/8 ligand resiquimod is also the subject of clinical investigations for the treatment of HSV infections (27). CpG DNA has been tested as a vaccine adjuvant showing good results (8). One of the most interesting clinical trials with CPG 7909 has been recently completed and aimed at comparing the immune responses after TLR9-boostered pneumococcal vaccination in human immunodeficiency virus-infected adults (Immune Response to Toll-Like Receptor 9-Agonist Adjuvanted Pneumococcal Vaccination in HIV Infected Adults - Full Text View - ClinicalTrials.gov ).

Therefore, the agonists used in the present study or related compounds could be of value as adjuvants to improve the efficiency of the local immune system of the CNS against bacteria. In the pharmacological administration of TLR agonists as adjuvants, the dose, timing, and duration of the immunotherapy, as well as the route of administration, have to be selected not only to maximize the benefit of the enhancement of the immune response but also to restrict an excessive induced response that might lead to autoimmune diseases or increased neuronal injury (4).

One clear advantage of using TLR agonists as adjuvants for the prophylaxis of bacterial meningitis is the low risk of development of resistance to the compound. For microglial activation, agonists with a low molecular mass would be preferable because of their higher penetration across the BBB (4). The entry of LPS into the central nervous compartments is minimal (5).

In conclusion, stimulation of TLRs increases phagocytosis of Gram-positive S. pneumoniae by microglia. Stimulation of the TLR system may be a therapeutic approach to protect the brain from invading pathogens. Further studies in immunocompromised mice are in progress in order to assess whether the resistance of the brain against infections can be increased by priming microglial cells with TLR agonists.

Toll-like receptor 4 agonist and antagonist lipopolysaccharides modify innate immune response in rat brain circumventricular organs
Toll-like receptor 4 agonist and antagonist lipopolysaccharides modify innate immune response in rat brain circumventricular organs - Journal of Neuroinflammation
The circumventricular organs (CVOs) are blood-brain-barrier missing structures whose activation through lipopolysaccharide (LPS) is a starting point for TLR-driven (Toll-like receptors) neuroinflammation. The aim of this study was to evaluate in the CVO area postrema (AP), subfornical organ (SFO), and median eminence (ME), the inflammatory response to two TLR4 agonists: LPS from Escherichia coli (EC-LPS), the strongest endotoxin molecule described, and LPS from Porphyromonas gingivalis (PG-LPS), a pathogenic bacteria present in the periodontium related to neuroinflammation in neurodegenerative/psychiatric diseases. The response to LPS from the cyanobacteria Rhodobacter sphaeroides (RS-LPS), a TLR4 antagonist with an interesting anti-inflammatory potential, was also assessed.
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Lipid A structures synthesized by other families of bacteria, with less fatty acyl chains and/or lack of 4’-phosphate are considered weak TLR4 agonists or TLR4 antagonists [12, 14]. An excellent example of this is the LPS from Porphyromonas gingivalis (PG-LPS), a weak TLR4 agonist, with a pentaacyl lipid A, less endotoxic properties compared to EC-LPS that induces the expression of TNF-α, IL-1β, and MIP-2, but not IL-12 p40 and IFN-γ [13], but with significant relevance in the inflammatory response in periodontal disease. Recently, inflammation derived from periodontitis has been related to the neuroinflammation state in neurodegenerative [15] and psychiatric diseases [16, 17]. Oral infection with P. gingivalis in mice can produce an impairment of learning and memory abilities by the release of pro-inflammatory cytokines in the brain [18], as well as depression-like behavior and a reduction of brain-derived neurotrophic factor (BDNF )[19]. A PG-LPS i.p. injection in rodents can lead to impairments in learning and memory tasks, and to an increase of inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-8) in brain cortex and activation of microglia and astrocytes in both hippocampus and brain cortex [20].
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On the other hand, a potent TLR4 antagonist in rodents and humans is the LPS synthetized by the cyanobacteria Rhodobacter sphaeroides [21]. Lipid A of RS-LPS does not induce cytokine expression because its signal transduction is not carried out; consequently, NF-κB is not translocated to the nucleus [13]. This bacterium has no relevance as a pathological microorganism; however, its LPS has been widely used as a blocker of TLR-4 to prevent inflammatory response in the presence of the highly endotoxic EC-LPS and it has been proposed as a neuroprotective strategy to prevent neuroinflammation [22, 23]. Microglial activation by EC-LPS in slices of the corpus callosum was correlated with axonal malfunction and with the accumulation of β-amyloid precursor protein in nerve fibers and a double treatment with EC-LPS and RS-LPS inhibited TLR-4 pathway activation and reversed microglial activation [24]. Using RS-LPS in an experimental model of epilepsy to block TLR-4 and to inhibit the release of pro-inflammatory mediators by microglia and astrocytes, excitability decreased in seizure threshold [25]. In experiments of nociception through chronic constriction injury to the sciatic nerve, the blockade of TLR-4 using RS-LPS by repeated intrathecal administration, attenuated allodynia and hyperalgesia [26]. On the contrary, in mouse primary microglia cultures, it was observed that RS-LPS can develop TLR-4 agonistic properties inducing the release of cytokines and chemokines [27].

Based on this evidence, we suggest that the presence of LPS molecules in the bloodstream derived from different gram-negative species and with distinct endotoxic properties modifies immediately the activity of the innate immune-mediated intracellular pathways in the first line of immune defense in the brain, the CVO’s. The present study aimed to evaluate the effects on CVOs neuroinflammatory response (NF-κB and microglia activation) of the weak TLR4 agonist PG-LPS and the TLR4 antagonist RS-LPS in comparison with the very well-known neuroinflammatory trigger and strongest TLR4 agonist EC-LPS.
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This study provides evidence about how bacterial LPSs with different endotoxic properties cause distinct effects on CVOs. Most of the experimental (in vivo or in vitro) studies use LPS derived from E. coli (the highest endotoxic molecule) as an neuroinflammatory inducer; however, in physiological conditions, CVOs might be exposed to LPSs from different gram-negative species present in gut, mouth, or skin microbiota, each of them with different compositions and structures, and with potential to induce high or low inflammatory responses.
 
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Combination of TLR2 and TLR3 agonists derepress infectious bursal disease virus vaccine-induced immunosuppression in the chicken
Combination of TLR2 and TLR3 agonists derepress infectious bursal disease virus vaccine-induced immunosuppression in the chicken - Scientific Reports
Live intermediate plus infectious bursal disease virus (IBDV) vaccines (hot vaccines) are used for protection against the virulent IBDV strains in young chickens. We evaluated the potential of Toll-like receptor (TLR) agonists to alleviate hot vaccine-induced immunosuppression. The combination of Pam3CSK4 and poly I:C synergistically upregulated IFN-β, IFN-γ, IL-12, IL-4, and IL-13 transcripts and cross-inhibited IL-1β, IL-10, and iNOS transcripts in the chicken peripheral blood mononuclear cells (PBMCs) as analyzed by quantitative real-time PCR. Further, four-week old specific pathogen free White Leghorn chickens (n = 60) were randomly divided into six groups and either immunized with hot IBDV vaccine with or without Pam3CSK4 and/or poly I:C or not vaccinated to serve as controls. The results indicated that poly I:C alone and in combination with Pam3CSK4 alleviated vaccine-induced immunosuppression, as evidenced by greater weight gain, increased overall antibody responses to both sheep erythrocytes and live infectious bronchitis virus vaccine, upregulated IFN-γ transcripts and nitric oxide production by PBMCs (P < 0.05), and lower bursal lesion score in the experimental birds.

The Involvement of TLR2 and TLR4 in Cytokine and Nitric Oxide Production in Visceral Leishmaniasis Patients before and after Treatment with Anti-Leishmanial Drugs
The Involvement of TLR2 and TLR4 in Cytokine and Nitric Oxide Production in Visceral Leishmaniasis Patients before and after Treatment with Anti-Leishmanial Drugs
Toll-like receptors (TLRs) have significant involvement in Leishmania infection, although little is known about the relationship between these receptors, cytokines and nitric oxide (NO) in patients with visceral leishmaniasis (VL) before or after treatment with anti-leishmanial drugs. The goal of this study was to evaluate the expression of TLR2 and TLR4 in CD3+ and CD14+ cells and the production of TNF-α, IFN-γ, IL-17, IL-10, TGF-β and NO in peripheral blood mononuclear cells (PBMCs) from VL patients pre- and post-treatment with anti-leishmanial drugs. In addition, we investigated whether these receptors were involved in the production of these cytokines and NO. In the active VL patients, increased TLR2 and TLR4 expression in lymphocytes and monocytes, increased production of TNF-α, IL-10 and TGF-β and decreased production of IFN-γ, IL-17 and NO were observed. After treatment, TLR2 and TLR4 were still expressed in lymphocytes and monocytes, the TNF-α and IL-10 levels were lower, the production of IFN-γ, IL-17 and NO was higher, and the TGF-β level remained high. Before treatment, the production of TNF-α and NO was associated with TLR2 and TLR4 expression, while IL-10 production was only associated with TLR2 expression. After treatment, both receptors were associated with the production of TNF-α, IFN-γ, IL-10 and NO, while the production of IL-17 was associated only with TLR4 expression. The results presented in this study suggest that both TLR2 and TLR4 participate in the modulation of cytokine and NO production in VL patients, contributing to the pathogenesis of VL prior to treatment and the protective immune response after treatment.

TLR Signaling on Protozoan and Helminthic Parasite Infection
TLR Signaling on Protozoan and Helminthic Parasite Infection

Toll-like receptors (TLRs), a major component of innate immune system, are expressed as membrane or cytosolic receptors on neutrophils, monocytes, macrophages, dendritic cells (DCs), B lymphocytes, Th1, Th2, and regulatory T lymphocytes. It recognizes pathogen-associated molecular patterns (PAMPs) and Toll-interleukin1 (IL-1) receptor (TIR) of various invading pathogens. Downstream signaling of TLRs activates NF-κB, which acts as a transcription factor of pro-inflammatory cytokines, chemokines, and costimulatory molecules. A balance between pro- and anti-inflammatory cytokine protects host body from infectious agents and also induces the healing process. Some of parasitic infections by protozoans and helminths such as Malaria, Leishmaniasis, Trypanosomiasis, Toxoplasmosis, Amoebiasis, Filariasis, Schistosomiasis, Ascariasis, Taeniasis, and Fasciolosis are the leading cause of death and economic loss in both developing and developed nations. Frequent exposure to parasites, immigration, refugee resettlement, increasing immunodeficiency, climate change, drug resistance, lack of vaccination, etc. are the major cause of emerging and re-emerging of the above-stated diseases. However, TLR activation by parasites could stimulate antigen presenting cells and ultimately clear the pathogens by phagocytosis. So, a better understanding of host-parasite interaction in relation to TLR signaling pathway will improve the controlling method of these pathogens in immunotherapy.
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Among the two types of vertebrate immune system, innate immunity provides the first line of defense against parasites. Previous studies stated innate immunity as nonspecific response, and it induces the acquired immunity (slower and specific response) by providing pathogens to T and B cells [5]. However, recent evidence proved that innate immune system also had a great degree of specificity and can provide host defense against invading parasites. This is because of the presence of five classes of pattern recognition receptors: TLRs (Toll-like receptors), C-type lectin receptors, NOD-like receptors (nucleotide-binding oligomerization domain leucine-rich repeat-containing receptors), RIG-I (retinoic acid inducible gene I protein) helicase receptors, and cytosolic dsDNA sensors [6, 7]. Among them, TLRs form a bridge between innate and adaptive immunity and play a very important role in parasite eradication. TLRs recognize specific pathogen-associated molecular patterns (PAMPs) in pathogens and initiate opsonization, phagocytosis, pro-inflammatory and anti-inflammatory response, and apoptosis [7, 8].
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TLRs present on dendritic cells (DCs) [both myeloid DCs (mDCs) and plasmacytoid DCs (pDCs)], neutrophils, macrophages, natural killer (NK), and natural killer T (NKT) cells induce dendritic cell maturation, MHC molecule upregulation, and costimulatory molecule production (CD40, CD80, and CD86) [21, 22]. The cytokines released by TLR signaling ultimately activate Th1 cells (via IL-12 from DCs) and Th2 cells (via IL-4 from B cell) [21, 23].
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TLR signaling occurs via two separate pathways: MyD88 (myeloid differentiation primary response protein)-dependent pathway and MyD88-independent pathway.

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In conclusion, induction of TLR signaling pathway by infectious pathogen recognition provides a better understanding of innate immune defense mechanism against this disease. Immunotherapy emerges as a promising therapeutic approach for parasitic infection treatment over the past few years.
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Although no effective drugs have emerged, vaccine adjuvants yield promising results due to induction of cellular immunity via TLR. Large scales of clinical studies were conducted for developing potent and well-tolerated adjuvants. The protozoan and helminth parasites can cause activation (to a small degree) and negative regulation (to a larger degree) of TLRs resulting in increasing or decreasing parasite burden [103]. TLR agonists or antagonists are small molecule mimics, natural ligands used for treating Type I allergy, cancer, and infectious diseases. MF59 (Novartis) and AS04 (GSK) are some examples of TLR4 agonist licensed for human use [124]. GLA (TLR4 ligand) and 3M-052 (TLR7/8) ligands are now in clinical trial. Recently, RTS,S/AS01, a recombinant chimeric protein (c-terminal of circumsporozoite antigen fused with HPB antigen, and “ASO1” refers to the adjuvant formulation MPL and QS21, a natural glucoside), is used for treating Malaria [125]. Several new drugs have been chemically synthesized for better understanding of the interaction of TLRs with their ligands. The knowledge from these studies will provide a greater opportunity for developing plant-derived new therapeutic drugs. So, major efforts are required for targeting TLRs in pathological conditions.
 
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Lactoferrin works as a new LPS-binding protein in inflammatory activation of macrophages
Lactoferrin works as a new LPS-binding protein in inflammatory activation of macrophages - PubMed

Though lactoferrin (LF) is a glycoprotein that is involved in immunomodulation, its action mechanism has not been fully elucidated. Previous studies have suggested that lipopolysaccharide (LPS) activity is inhibited by direct binding between LPS and LF. However, here we show that when LPS and purified LF was mixed, and formed a complex (termed as LF-LPS), it was found to induce production of inflammatory mediators in macrophages to some extent, rather than inhibit LPS activity. Moreover, when macrophages were pretreated with LF-LPS, cells were rendered a tolerant state to LPS challenge. These macrophage-activating effects were mediated by Toll-like receptor 4 (TLR4)-NF-kappaB pathway. Comparative studies with C3H/HeN and C3H/HeJ mice demonstrated the strong dependency of the LF-LPS signal on TLR4. These findings suggest that the immunomodulatory properties of LF could be due, in part, to LPS binding.

Endotoxin (Lipopolysaccharide, LPS) is a predominant glycolipid in the outer membrane of Gramnegative bacteria. LPS stimulates immune responses, including cytokine production, increase of expression of cell adhesion molecules, and proinflammatory mediator secretion by monocytes, macrophages, and neutrophils, which are recruited into specific host tissues by systemic LPS exposure. LPS also contributes to the systemic changes seen in septic shock. The response of the host to LPS is mediated by immune modulator molecules such as tumor necrosis factor a (TNF-a), members of the interleukin (IL) family, reactive oxygen species, and lipids. Overproduction of those mediators induces tissue damage that precedes multiple organ failure [1 –3]. Although there is great compositional variation among endotoxin derived from different bacterial serotypes, all endotoxins share a common structural principle. Endotoxins are amphiphilic molecules consisting of a hydrophilic polysaccharide component and a covalently bound hydrophobic lipid component, termed lipid A, a toxic portion of LPS [4]. A necessity for the activation of cells by LPS is its interaction with LPS-binding molecules. For example, LPS binds to LPS-binding protein (LBP) through the lipid A moiety, and the LPS –LBP complex is then recognized by CD14, which accelerates LPS priming of neutrophils [5]. However, there are still various molecules that are responsible for the LPS recognition and signal mediation in various cell types, and the physiological relevance of these molecules is not studied so far. Lactoferrin (LF) is an iron-binding glycoprotein that is present in high concentrations in milk secreted by the mammary gland, which provides protection to the neonate. Exocrine secretions like tears, saliva, and synovial fluids contain LF [6]. LF is also synthesized and released by mucosal epithelia and neutrophils in response to inflammatory stimuli [7,8]. LF activates macrophages and induces inflammatory cytokines, including IL-8, TNF-a and nitric oxide [9], though the mechanisms of these actions are not well established. The oral administration of LF induces IL-18 secretion by epithelial cells that act to enhance of Th1 cell functions and augment NK cells and cytotoxic lymphocyte activities [10]. These biological activities of LF depend on its target cells, and arise from its ability to bind to molecules. Structurally, LF contains a highly basic region close to the N terminus which binds to a variety of anionic biological molecules, including lipid A. LF binds to lipid A with high affinity (Kd = 2 – 5 nM) [11], and this LPS-binding property of LF should be considered to be part of the immunomodulatory function of LF.

Most previous studies have reported that LF can inhibit LPS activity by direct binding with high affinity [12 – 14], or by competition with LBP for the LPS binding and therefore interferes with the interaction of LPS with CD14 [15].

However, there are some reports to the effect that LF has no effect on LPS activity: LF did not inhibit LPS-mediated stimulation of macrophages [16], or even inactivated LPS by LF from neutrophil still gelled Limulus assay and primed monocytes [17]. Thus, in this study, we investigated the effects and mechanisms of LF and LPS action on macrophages. We found that the LF–LPS complex still activated macrophages and even induced tolerance to LPS stimulation. We found that LF–LPS complex did not exhibit its effects in the macrophages of C3H/HeJ mice, indicating that LF–LPS complex activates macrophage through Toll-like receptor 4 (TLR4).

Interestingly, LPS-stimulated NO and TNF-a production were significantly inhibited in the LF–LPS-pretreated groups (Fig. 2B).

RT-PCR for IL-1h and IL-6 was also performed, and found that these genes expressions were down-regulated in the presence of LPS challenge. These results suggested that when macrophages are pretreated for an extended period with LF –LPS, they are rendered tolerant to LPS challenge.

The Protective Effects of Lactoferrin Feeding against Endotoxin Lethal Shock in Germfree Piglets
The Protective Effects of Lactoferrin Feeding against Endotoxin Lethal Shock in Germfree Piglets

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Bovine lactoferrin free of lipopolysaccharide can induce a proinflammatory response of macrophages
Bovine lactoferrin free of lipopolysaccharide can induce a proinflammatory response of macrophages

Lipopolysaccharide-inactivating activity of neutrophils is due to lactoferrin
Lipopolysaccharide-inactivating activity of neutrophils is due to lactoferrin - PubMed
Neutrophils can inactivate lipopolysaccharide (LPS), thereby blocking the ability of LPS to prime fresh neutrophils for enhanced fMLP-triggered release of superoxide. Here we show that inactivation of LPS by neutrophils was primarily due to lactoferrin. A time course for inactivating LPS showed that neutrophils (5 million/ml) took 30 min to inactivate 10 ng/ml LPS.

Reciprocal Interactions between Lactoferrin and Bacterial Endotoxins and Their Role in the Regulation of the Immune Response
Reciprocal Interactions between Lactoferrin and Bacterial Endotoxins and Their Role in the Regulation of the Immune Response
Overall, LPS-binding property of Lf plays an important role in the immunomodulatory activity of this molecule offering a dual advantage. In fact, from one side, Lf can sequester LPS, thus inhibiting the excessive host’s response to endotoxin challenge, and from the other, can take advantage of the LPS bound to its molecule to trigger an immune response engaging specific LPS receptors.

Lactoferrin-lipopolysaccharide (LPS) binding as key to antibacterial and antiendotoxic effects
Lactoferrin-lipopolysaccharide (LPS) binding as key to antibacterial and antiendotoxic effects
Lactoferrin (Lf), a multifunctional protein of the innate immune response, seems to act as a permeabilizing agent of Gram negative bacteria, apparently due to its interaction with enterobacterial lipopolysaccharide (LPS) on the bacterial surface. In both human and bovine Lf, a six residue sequence lying in an 18-loop region of the lactoferricin domain is key to Lf–LPS binding. There is much evidence that, by its action on LPS, Lf destabilizes the bacterial membrane and therefore increases bacterial permeability. By itself, Lf is not an effective antibacterial agent, but it permits the penetration of the bacterial membrane by some antibacterial substances whose hydrophobicity otherwise limits their efficacy. Additionally, Lf neutralizes free LPS by keeping the latter from forming complexes that activate TLR-4 signaling pathways. Such pathways, when over-activated, lead to the abundant production of pro-inflammatory mediators such as tumor necrosis factor (TNF) with fatal consequences to the host. The effect of Lf in reducing inflammation and destabilizing Gram negative bacteria has clinical implications in the control of sepsis, multiple organ dysfunction and bacterial invasion.

Lactoferrin in Aseptic and Septic Inflammation
Lactoferrin in Aseptic and Septic Inflammation
Lactoferrin (Lf), a cationic glycoprotein able to chelate two ferric irons per molecule, is synthesized by exocrine glands and neutrophils. Since the first anti-microbial function attributed to Lf, several activities have been discovered, including the relevant anti-inflammatory one, especially associated to the down-regulation of pro-inflammatory cytokines, as IL-6. As high levels of IL-6 are involved in iron homeostasis disorders, Lf is emerging as a potent regulator of iron and inflammatory homeostasis. Here, the role of Lf against aseptic and septic inflammation has been reviewed. In particular, in the context of aseptic inflammation, as anemia of inflammation, preterm delivery, Alzheimer’s disease and type 2 diabetes, Lf administration reduces local and/or systemic inflammation. Moreover, Lf oral administration, by decreasing serum IL-6, reverts iron homeostasis disorders. Regarding septic inflammation occurring in Chlamydia trachomatis infection, cystic fibrosis and inflammatory bowel disease, Lf, besides the anti-inflammatory activity, exerts a significant activity against bacterial adhesion, invasion and colonization.
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Lastly, a critical analysis of literature in vitro data reporting contradictory results on the Lf role in inflammatory processes, ranging from pro- to anti-inflammatory activity, highlighted that they depend on cell models, cell metabolic status, stimulatory or infecting agents as well as on Lf iron saturation degree, integrity and purity.
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Lactoferrin Against Inflammation Related to Cystic Fibrosis Lung Infection

Cystic fibrosis (CF) is a multi-system genetic disorder affecting several organs and reducing expectancy and quality of life. The most relevant damages are observed in the airways, that are characteristically susceptible to infections, principally, but not only, due to Pseudomonas aeruginosa [190,191]. During CF-induced airway infection progress, P. aeruginosa gradually shifts from the virulent form typical of early stage of infection towards the host-adapted form distinctive of the chronic phase, characterized by biofilm lifestyle, and antibiotic resistance [192].

Moreover, a massive airways inflammatory response is usually observed in CF subjects, which is already active before bacterial colonization, as evidenced by high levels of IL-8 and neutrophils’ accumulation in bronchoalveolar lavage (BAL) [193]. In general, the inflammatory status is activated by an over-expression of NF-κB and activator protein (AP)-1, leading to an up-expression of pro-inflammatory cytokines [194,195,196]. As a matter of fact, the massive recruitment of leukocytes into the lung airways gives rise to a self-enhancing loop, where the infiltrated neutrophils undergo necrosis and release proteases and chemoattractant molecules, thus leading to tissue damage and to the further recruitment of leukocytes.

Therefore, therapeutic strategies need to be addressed not only to counteract lung infection but also inflammatory processes and immunity disorders in CF patients.

In this respect, bLf has been used to decrease P. aeruginosa load and inflammation in in vitro and in vivo studies. In a paper by Frioni et al. [197], the addition of bLf to a primary human CF airway epithelium did not influence P. aeruginosa LESB58 adhesion, but significantly decreased intracellular bacterial number. In addition, bLf was able to reduce inflammatory response by infected bronchial epithelium by down-regulating the levels of IL-1β, IL-6 and IL-8 [197].

molecules-24-01323-g002.jpg

Schematic representation of the lactoferrin anti-inflammatory effects in different aseptic (red arrows) or septic (blue arrows) inflammatory pathologies. Lower and upper arrows indicate parameters decreased or increased, respectively.
 
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Acute modulation of toll-like receptors by insulin
Acute modulation of toll-like receptors by insulin - PubMed
Results: Insulin infusion significantly suppressed TLR1, -2, -4, -7, and -9 mRNA expression in MNCs within 2 h of the infusion, with a maximum fall at 4 h by 24 +/- 9%, 21 +/- 5%, 30 +/- 8%, 28 +/- 5%, and 27 +/- 10% (P < 0.05, for all), respectively, below the baseline. TLR2 protein was suppressed by 19 +/- 7% (P < 0.05) below the baseline at 4 h. The DNA binding of PU.1, a major transcription factor regulating many TLR genes, was concomitantly suppressed by 24 +/- 10% (P < 0.05) by 4 h in MNCs. There was no change in TLR expression or DNA binding by PU.1 following dextrose or saline infusion in the control groups.
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Since TLR4 mediates the inflammatory response to endotoxin, it is possible that insulin may potentially reduce the inflammatory response to endotoxin by reducing the receptor population binding to endotoxin, provided we can demonstrate a reduction in TLR4 protein expression with longer infusions in the future. This effect would be in addition to the more direct anti-inflammatory effect of its own through the suppression of NFκB and early growth response factor-1, two major proinflammatory transcription factors. Such an additional effect may be of considerable importance since inflammation triggers an increase in TLR expression and thus provides a positive feedback for inflammation. This positive feedback, which may lead to a more protracted and intense inflammation, would potentially be prevented by insulin. A direct anti-inflammatory effect of insulin and its additional ability to suppress TLR expression provide it a profoundly potent combination in combating inflammatory processes. The suppression of TLR2 expression at mRNA and protein level by insulin is relevant to gram-positive bacterial infections. These actions of insulin may have contributed to the beneficial effects of insulin observed by Langouche et al. (22) in patients in critical care. It is also relevant that a similar low dose of insulin infusion causes a reduction of 40% in plasma CRP and SAA concentrations within 24 h in acutely ill patients with acute myocardial infarction (3) and in patients undergoing coronary artery bypass surgery (4). Whether a significant part of this suppression of CRP and SAA and the cardioprotection observed in acute myocardial infarction receives a contribution from a reduction in TLR2 expression needs to be carefully assessed in the future.

Recent work (23) has shown that in atherosclerosis, the expression of TLR1, -2, and -4 in the arterial intima is increased, especially in areas with inflammatory infiltration. The increase in TLR2 and TLR4 expression is associated with an increase in intranuclear NFκB. Several TLR4 ligands, such as oxidized LDL, human heat shock protein-60 and -70, and peptidoglycan are found in atherosclerotic plaques. They may activate NFκB and cause a release of cytokines and matrix metalloproteinases. This indicates that insulin action on TLR expression might play a role in atherosclerosis suppression and potential prevention of plaque rupture.

Active pharmaceutical research aiming to reduce TLR4 expression to prevent the proinflammatory action of LPS is currently being undertaken. This includes an attempt to generate antibodies against TLR4. The rapid suppression of TLR2 and TLR4 expression by insulin implies that insulin can be used clinically in endotoxemia and gram-negative (TLR4) and gram-positive (TLR2) infections to limit their inflammatory effects. Furthermore, the involvement of TLR2 in ischemia-reperfusion injury (11) and that of TLR4 in atherogenesis further justifies the use of insulin in acute and chronic atherosclerotic syndromes. In this context, the ability of insulin to suppress CRP is also relevant, since CRP mediates injury during ischemia-reperfusion of the heart and synthetic small molecules (phasphotidyl choline derivatives), which bind to and block CRP action and reduce the size of myocardial injury (24).

In conclusion, insulin suppresses TLR expression and the activity of the transcription factor PU.1. The suppressive effect of insulin on TLRs also has important potential implications in the treatment of inflammatory conditions including endotoxemia, other infections, and acute coronary syndromes in which TLR2-related mechanisms are involved. The suppressive effect of insulin on TLR4 is also important in understanding the relationship of inflammation to obesity and insulin resistance and atherosclerosis.

Insulin Suppresses Endotoxin-Induced Oxidative, Nitrosative, and Inflammatory Stress in Humans
Insulin Suppresses Endotoxin-Induced Oxidative, Nitrosative, and Inflammatory Stress in Humans
LPS injection induced a rapid increase in plasma concentrations of nitric oxide metabolites, nitrite and nitrate (NOM), and thiobarbituric acid–reacting substances (TBARS), an increase in reactive oxygen species (ROS) generation by polymorphonuclear leukocytes (PMNLs), and marked increases in plasma free fatty acids, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), macrophage migration inhibition factor (MIF), C-reactive protein, resistin, visfatin, lipopolysaccharide binding protein (LBP), high mobility group-B1 (HMG-B1), and myoglobin concentrations. The coinfusion of insulin led to a total elimination of the increase in NOM, free fatty acids, and TBARS and a significant reduction in ROS generation by PMNLs and plasma MIF, visfatin, and myoglobin concentrations. Insulin did not affect TNF-α, MCP-1, IL-6, LBP, resistin, and HMG-B1 increases induced by the LPS.
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Insulin reduces significantly several key mediators of oxidative, nitrosative, and inflammatory stress and tissue damage induced by LPS. These effects of insulin require further investigation for its potential use as anti-inflammatory therapy for endotoxemia.
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Insulin has been shown to suppress inflammatory changes in vitro and in vivo. It suppresses intranuclear NFκB and Egr-1 binding and the expression of several proinflammatory mediators including intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase-9, C-reactive protein (CRP), and serum amyloid A (3,4). In addition, it suppresses the expression of several Toll-like receptors (TLRs) (5). It also suppresses reactive oxygen species (ROS) generation and p47phox expression.
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Our data clearly show for the first time a potent and rapid suppressive effect of a low dose of insulin infusion on the expression of TLR1, -2, -4, -7, and -9 by 20–30%, evident at 2 h, continuing until 4 h, and reverting back to baseline 2 h after the cessation of infusion. This low-dose infusion of insulin has previously been shown to exert a rapid and profound anti-inflammatory effect within 2 h, as reflected in the suppression of NFκB binding and an increase in inhibitor of κBα expression. The fall in TLR2 mRNA was also associated with a reduction in the expression of TLR2 protein. The absence of a clear suppression of TLR4 protein level may be due to the relatively short period of infusion. This issue should be addressed in the future by longer periods of infusion. Our data also demonstrate clearly for the first time that insulin rapidly suppresses the DNA binding of PU.1 to a specific sequence of TLR4 gene promoter. PU.1 is a key transcription factor in the regulation of TLR transcription, and, thus, its suppression is reflected in the suppression of many of TLRs to a similar extent. The pattern of fall in TLR mRNA expression was similar to that observed with other proinflammatory mediators like MCP-1 and sICAM-1, which fell at 2 h, remained low for the duration of the infusion, and returned to baseline at 6 h, 2 h after the cessation of the insulin infusion. This is also consistent with our previous data on the suppressive effect of insulin on other indexes of inflammation. Thus, there is a remarkable consistency in the pharmacodynamics of the various aspects of the anti-inflammatory effects of insulin.
 

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