Aspirin in the context of Endotoxin Tolerance

bigc

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Summary of studies:

Endotoxin tolerance (ET) is a reduced responsiveness to a LPS challenge following a first encounter with endotoxin. Chronically, this may lead to local or systemic immunosuppression. Despite ongoing low-grade tissue irritation, only a blunted immune response is mounted. On re-stimulation following ET, the inflammatory cytokines (and chemokines) like TNF-α, IL-6, IL-1β, IL-12 were downregulated, anti-inflammatory cytokines (and chemokines) like IL-10, TGF-β, IL-1RA were upregulated.

This is not only a downregulation of LPS-induced gene expression but an also an upregulation of anti-inflammatory mediators that inhibit the TLR4 dependent signaling pathway. This presents a picture of 'gene reprogramming', giving rise to immune amnesia. ET is associated with increased resistance to subsequent injury and even mortality. Simultaneously, it is associated with impaired resistance to further infectious challengers. This suggests that ET is an adaptive immunosuppressive mechanism that cannot clearly be said to always be good or bad.

In neuroinflammation, ET preconditioning attenuated pro-inflammatory cytokine expression in a subsequent greater challenge. The blunted response may be due to immune exhaustion as ET macrophages have been shown to have decreased cellular metabolism and appear to have transitioned to a survival state. This brings evidence against any claim that ET may be a 'trained immunity'.

Aspirin is commonly known as an anti-inflammatory that inhibits the production of prostaglandins. Low dose aspirin has been associated with surviving septic shock. Counter-intuitively, this has been attributed its pro-inflammatory effects instead. As protaglandins attenuate pro-inflammatory cytokine production, it is proposed that inhibition of prostaglandin production leads to a pro-inflammatory cytokine response. In addition it is speculated that COX1 inhibition also results in enhanced production of isoprostanes. Is it possible that the benefits of aspirin in sepsis are due to be from more effective early clearance of bacteria and counteracting sepsis-induced immunoparalysis.

My added thoughts:

Simply put, in the context of innate immunity the body hopes to have cleared the injury the first time it raises an immune response. It musters up the best it can in response to the initial insult since subsequent responses may be blunted due to exhaustion.

If clearance of the first insult does not protect the body from encountering a second insult, then clearance of the second could just lead to a third and so on. Rather than repeatedly throwing resources at possibly unrelenting insults and burning out so to speak, the body dampens inflammation and chooses flight over fight. Reasoning that if its best defence was inadequate, it instead needs to redirect resources towards physically removing itself from the threat.

Excerpts from studies:
Bench-to-bedside review: Endotoxin tolerance as a model of leukocyte reprogramming in sepsis (2006)
Endotoxin tolerance is defined as a reduced responsiveness to a lipopolysaccharide (LPS) challenge following a first encounter with endotoxin... Endotoxin tolerance is accompanied by the up-regulation of inhibitory molecules that down-regulate the Toll-like receptor (TLR)4-dependent signaling pathway.

Paul Beeson first reported endotoxin tolerance in 1946 [1] as the abolition of the fever response of rabbits undergoing repeated daily injection of the same dose of typhoid vaccine... Not only can a pretreatment with endotoxin reduce subsequent lipopolysaccharide (LPS)-induced fever in rabbits, it also prevents LPS-induced lethality [8]. In mice, even when LPS-induced lethality was dramatically enhanced by galactosamine treatment, LPS tolerization could prevent mortality [9].

It is worth recalling that endotoxin tolerance has been associated with increased resistance and protection against tissue injuries and even mortality in models such as infected thermal injury [16], hepatic ischemia/reperfusion [17], renal ischemia/ reperfusion [18], coronary occlusion [19], or hemorrhagic shock [20].

In contrast, some studies suggested that the induction of endotoxin tolerance might impair resistance to infectious processes. For example, a reduced level of IFN was reported in animals pretreated with LPS and further challenged with Newcastle disease virus [21]. Moreover, a reduced leishmanicidal activity was observed after pre-exposure of macrophages to LPS [22], and an impaired lung clearance of Pseudomonas aeruginosa was shown after LPS exposure [23].

An altered responsiveness of circulating human monocytes has been regularly reported in sepsis patients. IL-1α, IL-1β, IL-6, and TNF production upon ex vivo activation of patients’ monocytes were significantly reduced in response to LPS [26]. Normal reactivity was never restored in non-surviving patients in contrast to those who recovered. This altered ex vivo cytokine production was reproduced in human volunteers receiving an injection of LPS [27].

Endotoxin tolerance: new mechanisms, molecules and clinical significance (2009)
Prior exposure of innate immune cells like monocytes/macrophages to minute amounts of endotoxin cause them to become refractory to subsequent endotoxin challenge, a phenomenon called ‘‘endotoxin tolerance’’. Clinically, this state is associated with monocytes/macrophages in sepsis patients where they contribute to ‘‘immunosuppression’’ and mortality.

While detection of pathogens and/or endotoxins by innate immune cells triggers a robust and essential inflammatory reaction, this process needs to be tightly regulated. Uncontrolled inflammation leads to extensive tissue damage and manifestation of pathological states like sepsis, autoimmune diseases, metabolic diseases and cancer [2].

Upon endotoxin re-challenge with gram-negative bacteria or LPS, monocytes/macrophages show a drastic downregulation of inflammatory cytokines (e.g. TNFa, IL-6, IL-1b, IL-12) but an upregulation of anti-inflammatory cytokines like IL-10, TGFb and IL-1RA as compared to non-tolerized cells challenged with the same stimuli. The tolerant monocytes/macrophages also show an impaired antigen presenting capacity correlated with decreased expression of HLA-DR and some co-stimulatory molecules [10]. In contrast, these cells show upregulated expression of a number of scavenging/C-type lectin receptors like MARCO, CD64, CLEC4a [10,11] is linked to enhanced phagocytic capacity

Monocytes respond to the systemic infection by triggering an inflammatory reaction characterized by overt levels of inflammatory cytokines and chemokines (e.g. TNFa and IL-6). However, as sepsis progresses, these monocytes become refractory to further endotoxin challenge whereby they fail to upregulate inflammatory cytokines. Instead, they start producing anti-inflammatory cytokines (TGFb, IL-10) which promote immunosuppression. Under these conditions, there is a high risk of developing secondary infections, which may lead to mortality [38]

While endotoxin tolerance (ET) has been thought of as a protective mechanism against septic shock and ischaemia, its incidence is associated with high risks of secondary infections. For example, in sepsis, mortality due to secondary infection is associated with the incidence of a tolerant state [15]. Similarly, in acute pulmonary syndromes and cystic fibrosis, ET relates to an increased susceptibility to nosocomial infections.

First, ET can be viewed as a negative feedback response arising as a result of dysregulated inflammation (e.g. sepsis). Second, ET is a case of gene reprogramming and immunomodulation rather than a global downregulation of gene expression and function. In this context, the use of the term ‘tolerance’ could be misleading... Finally, an endotoxin-tolerant state is [not] restricted to sepsis or SIRS, and is observable in many diseases, such as hepatic ischaemia, acute coronary syndrome, cystic fibrosis and perhaps even cancer.

Protective effects of endotoxin tolerance on peripheral lipopolysaccharide-induced neuroinflammation and dopaminergic neuronal injury (2022)
The hallmarks of neuroinflammation include the activation of microglia and the release of pro-inflammatory cytokines. These two factors have been shown to be involved in the development of neuronal degeneration.

The literature has confirmed that anti-inflammatory treatment is effective in neurodegenerative diseases such as Alzheimer’s disease and PD. However, the efficacy of non-steroidal anti-inflammatory drugs is uncertain, and toxic effects cannot be effectively avoided. Hence, nonsteroidal anti-inflammatory drugs failed to achieve wide application in central nervous system brain injury.

ET has been shown to alleviate the process of a variety of neurological diseases, including middle cerebral artery occlusion syndrome, brain trauma, and Alzheimer's disease. These results show that ET plays an important role in neuroprotection.

In this study, mice were injected intraperitoneally with low dose (0.5 mg/kg) LPS for 4 days to induce endotoxin tolerance (ET). Then, high-dose (1 mg/kg) LPS was injected continuously intraperitoneally for 4 days to induce Parkinson-like changes.

Results

To test whether ET preconditioning was able to prevent continuous peripheral high-dose LPS injection-induced neuroinflammation, we first investigated the expression of cytokines (TNF-α, IL-1β, and IL-10) in the SN by ELISA. Compared with the control group, continuous high-dose LPS administration (4 × LPS1 group) caused an increase in the TNF-α and IL-1β expression in the SN (p < .01 and p < .05, respectively). At the same time, the expression of the IL-10 was decreased (p < .01). The changes of cytokines in the 4 × LPS0.5 group were not statistically significant (all p > .05; Figure 3(a)). Compared with the 4 × LPS1 group, ET pretreatment significantly decreased the expression of TNF-α (39.63%, p < .01) and IL-1β by (15.86%, p < .05) and increased the expression of IL-10 (19.78%, p < .05) at 28 days postcontinuous high-dose LPS injection (Figure 3(a)).

Our results showed that ET preconditioning attenuated the continuous high-dose LPS injection-induced neuroinflammation, manifested as a decrease in pro-inflammatory cytokine expression.

LPS Tolerance Inhibits Cellular Respiration and Induces Global Changes in the Macrophage Secretome (2021)
We used metabolic measurements to confirm differences in the cellular metabolism of naïve macrophages and that of macrophages responding to LPS stimulation or those in the LPS-tolerant state. In parallel, we performed an unbiased secretome survey using quantitative mass spectrometry during the induction of LPS tolerance, creating the first comprehensive secretome profile of endotoxin-tolerant cells. The secretome changes confirmed that LPS-tolerant macrophages have significantly decreased cellular metabolism and that the proteins secreted by LPS-tolerant macrophages have a strong association with cell survival, protein metabolism, and the metabolism of reactive oxygen species.

While the lower cytokine production during LPS tolerance prevents a severe “cytokine storm” response and lethal effects in the host, decreased cytokine levels might not be sufficient to maintain an effective defense against pathogens. Indeed, LPS tolerance has been reported to be associated with the immune suppression stage known as immune exhaustion [ 6 ]. A concept of innate immunity bearing a memory of past insults termed “trained immunity” encompasses endotoxin tolerance.

We found that while a single LPS stimulation enhanced cytokine release (LPS-Responding (LR)), two sequential LPS stimulations over a 24-h period induced decreased cytokine levels following a 6-h incubation (LPS-Tolerant (LT)) (Figure 1A–C). These results established the conditions required to induce LPS tolerance in RAW cells.

Results

While the decrease in secretion could be due to many factors such as a lack of available amino acids to build proteins, inhibition of vesicle transport, or increased turnover of specific mRNAs, we hypothesized that LPS-tolerant cells would display changes in their metabolic functions. The glycolytic and mitochondrial functions of control (Con or NT), LR, and LT cells were determined by measuring the ECAR and OCR using the Seahorse XF Extracellular Flux Analyzer. Both functions were impaired in LT cells compared to Con or LR cells (Figure 2A–E). Hence, the lower macrophage cytokine production in LPS-tolerant cells compared with control cells might be associated with the low cell energy.

LPS-Responding RAW 264.7 cells’ secretomes include cytokines and signaling proteins strongly related to the inflammatory response and cell motility, while LPS-Tolerant RAW 264.7 cells’ secretomes include proteins strongly related to cell survival.

3.3. Pathway Analysis of Critical Groups
Because either increasing or decreasing secretion of a signaling protein could have profound effects on the condition of cells, we analyzed all proteins with significant changes.

When we focus on the myeloid cell responses, the differences in the LR and LT groups become even more striking. While the “Immune Response of Myeloid Cells” is significantly affected in either condition (p-values of <0.001), the LR condition had an increased response (z-score 1.134) but the LT condition had a decreased response (z-score −0.348)

Another biological function associated with all three sets and with the LPS response was cellular motility. Due to the variety of cells and mechanisms of movement, most analysis platforms include both general terms and specific pathways. In the LR group, “Cell Movement of Macrophages” was significantly increased (p-value < 0.001, z-score 2.829), and while the LT group had a highly significant increase (p-value < 0.001), the overall degree of migration was lower (z-score −0.290)... This suggests that both treatments lead to cellular migration, but the overall effect was much higher in the LPS-responsive group.

While the processes of inflammation and movement are critical for the immune response, cell survival has been the hypothetical goal of LPS tolerance. In support of this hypothesis, our results found significant inhibition of ”Cell Death of Immune Cells” in the LT group (p-value < 0.01, z-score −0.254) (Supplementary Table S2). In contrast, the LR group had a highly significant increase in the “Cell Death of Immune Cells” (p-value < 0.001, z-score 0.565) (Supplementary Table S2). The difference in the recovery of cell-survivalassociated proteins from the LT and LR groups suggests a connection between cell survival and LPS tolerance (Figure 6D).

We have hypothesized that cellular exhaustion is related to suppression of the LPS response in sequential LPS treatments. Two pathways that relate to exhaustion are metabolism and the production of reactive oxygen species.

Metabolism can be further defined by the class of molecule targeted, such as protein, lipid, or carbohydrate. The two classes that exhibited the clearest differences between the LR and LT groups were the processes related to carbohydrate and protein metabolism. In carbohydrate metabolism, the overall effect is that the LPS response induced increased carbohydrate metabolism, including the binding, accumulation, and metabolism of polysaccharides (Figure 8B). In contrast to the carbohydrate results, an examination of the processes related to protein metabolism showed increased association between the LT group and protein metabolism. roteins, with the increased z-score of overall protein metabolism an protein synthesis coinciding with decreases in protein catabolism and proteolysis (Figur 8C).

Overall, the LT group results were linked to lower metabolism and synthesis of ROS compared to the LR group (Figure 8D Supplementary Table S2). These results confirm the modifications in the cellular environment that occur during both the LPS response and LPS tolerance.

Correspondence: Aspirin may improve outcome in sepsis by augmentation of the inflammatory response (2016)
The authors hypothesize that the anti-inflammatory effects exerted by these drugs may explain the decreased mortality... However, for aspirin treatment we would like to argue that it is more likely that this is related to an augmented pro-inflammatory response rather than to anti-inflammatory effects.

Perhaps counter-intuitively, aspirin increases the proinflammatory cytokine response after whole blood stimulation with endotoxin in healthy volunteers [2].

As prostaglandins are known to attenuate (innate) pro-inflammatory cytokine production at the transcriptional level [4], it appears plausible that the pro-inflammatory effects of these COX inhibitors are mediated by attenuation of prostaglandin production. Therefore, patients on chronic low dose aspirin may exhibit an augmented pro-inflammatory cytokine response to invading pathogens. This enhanced initial cytokine response likely results in more effective clearance of bacteria [5], whereas an initially less pronounced pro-inflammatory cytokine response may result in ineffective microbial killing, leading to an increase of the bacterial load, ultimately causing more pronounced activation of the immune response, septic shock, organ failure, and increased risk of death [6].

Correspondence: Role of aspirin in patients with septic shock: a complex and intriguing relationship (2016)
our recent report in which we demonstrated that patients with community-onset pneumonia on treatment with macrolides plus low-dose aspirin have improved survival compared to untreated ones [2].

The intrigu- ing and provocative hypothesis of Kiers and colleagues may have another biologic plausibility, which has been demonstrated in a study performed in diabetic patients on chronic treatment with low-dose aspirin [3]. This study revealed that type II diabetic patients display an enhanced production of platelet F2-isoprostanes, which are chemically stable eicosanoids with pro-aggregating activity. Of note, F2-isoprostanes stem from arachidonic acid interaction with superoxide anion, which is a reac- tive oxidant species (ROS) formed by activation of Nox2, the enzyme of the innate immune system which is crucial for bacteria killing [3].

The authors speculated that, as a consequence of COX1 inhibition by aspirin, arachidonic acid is shifted towards Nox-2-derived ROS activation with ensuing enhanced production of isoprostanes [2].

Based on this obser- vation, it is possible that the improved survival by aspirin may be dependent on a paradoxical increase of inflam- mation, which is related not only to prostaglandin down- regulation but also to a pro-oxidant activity derived from Nox2 activation.

A randomised trial on the effect of anti-platelet therapy on the systemic inflammatory response in human endotoxaemia (2017)
To gain more insight into the immunomodulating properties of the various antiplatelet agents that are used for cardiovascular prevention, we aim to study the effect of low-dose ASA alone and in combination with the P2Y12 inhibitors clopidogrel and ticagrelor in a well-validated human in vivo model of systemic inflammation.

forty healthy male volunteers aged 18–35 years... Briefly, subjects were treated for seven days after a loading dose on day one. Loading dosages were 180, 300, and 160 mg, and maintenance dosing schedules were 90 mg b. i. d. [twice daily], 75 mg q.d [once daily] and 80 mg q.d for ticagrelor, clopidogrel, and ASA, respectively.

To evaluate the effects of low dose acetylsalicylic acid, we compared the cytokine response of subjects treated with ASA to the placebo treated group. Plasma levels of TNFα, IL-6, IL-8 and MIP-1α were increased to a greater extent in ASA-treated subjects compared with the placebo group, and there was a trend towards enhanced levels of MCP-1... None of the study treatments affected plasma concentrations of MIP-1β and the anti-inflammatory cytokines IL-10 and IL-1RA.

ASA, as a COX-inhibitor, abrogates the production of PGE2, and we and others have shown that PGE2 attenuates cytokine production (29). Furthermore, the addition of exogenous PGE2 dose-dependently prevents the pro-inflammatory of ASA (30). As such, ASA prevents PGE2 production and thereby abrogate it’s inhibitory effect on cytokine production.

These authors further demonstrate that platelets exert antiinflammatory effects through the activation of the COX-1-PGE2 pathway (32). Taken together, it is conceivable that the mechanism of the ASA-induced pro-inflammatory effects observed are caused by inhibition of PGE2 production by platelets. As a consequence, PGE2-induced dampening of pro-inflammatory cytokine responses is attenuated, ultimately resulting in increased cytokine levels.

Two hypothesis on how the immune-enhancing effects of ASA may contribute to any survival benefit in patients with sepsis may be put forward. First, the augmented pro-inflammation caused by low-dose ASA may result in a more effective early clearance of bacteria, resulting in improved survival compared to patients with an initial less pronounced cytokine response (43). Alternatively, the here described immune-enhancing effects of ASA could also explain the observed beneficial outcomes in sepsis if ASA counteracts sepsis-induced immunoparalysis

Sepsis-induced immunoparalysis is a phenomenon receiving increasing attention, characterised by the inability to clear pathogens and an increased susceptibility to secondary (opportunistic) infections (44). The immune-stimulating properties of ASA may partially compensate this immune refractant state.

In conclusion, seven days of treatment with low-dose ASA resulted in an enhanced pro-inflammation during systemic inflammation in humans.

Treatment With Acetylsalicylic Acid Reverses Endotoxin Tolerance in Humans In Vivo: A Randomized Placebo-Controlled Study (2019)
Healthy volunteers were challenged IV with endotoxin twice, at a 1-week interval... All subjects were challenged IV with endotoxin twice, on study days 7 and 14... Furthermore, monocytes of sepsis patients were incubated with acetylsalicylic acid preexposed platelets and were subsequently stimulated with endotoxin.

Sepsis-induced immunoparalysis is characterized by impaired innate and adaptive immune responses, including exhaustion and apoptosis of lymphocytes, diminished capacity of monocytes and macrophages to produce cytokines, and decreased HLA-DR expression on the cell surface of monocytes (5, 7, 8).

ASA treatment resulted in a distinct shift toward a more proinflammatory phenotype upon the second endotoxin challenge... In our study, the ASA-induced changes in cytokine levels/production in healthy volunteers in vivo (TNF-α: +53%, IL-6: +91%, IL-8: +42%, and IL-10: –40%) and in septic patients ex vivo (TNF-α: +66% and IL-10: –23%) were in the same order of magnitude or greater. Therefore, it appears plausible that the observed ASA-induced shifts are of clinical relevance.

This was inspired by PakPik's many posts on infection and aspirin.
 

EvanHinkle

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Wow, so, a lot of this is above my pay grade, but for the people in the back of the classroom like me, you’re saying if the inflammatory immune response is inadequate to rid the body of infection, (maybe after a few tries) the body, (as supported by some of the studies you linked) will begin to compensate to essentially live with the LPS?

Aspirin then plays a role in supplementing the immune response such that it signals the immune system to take another pro-inflammatory shot at the invaders so to speak. Coupled with tetracycline therapy the induced stasis of the bacteria makes it far more susceptible to the immune system in general, and more so in conjunction with aspirin?

Did I get the basics there? If so, that’s about the most incredible thing I’ve ever read, and would seem to align with just about everything I’ve learned/experienced so far.

Thanks in advance!
 
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bigc

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Wow, so, a lot of this is above my pay grade, but for the people in the back of the classroom like me, you’re saying if the inflammatory immune response is inadequate to rid the body of infection, (maybe after a few tries) the body, (as supported by some of the studies you linked) will begin to compensate to essentially live with the LPS?

Aspirin then plays a role in supplementing the immune response such that it signals the immune system to take another pro-inflammatory shot at the invaders so to speak. Coupled with tetracycline therapy the induced stasis of the bacteria makes it far more susceptible to the immune system in general, and more so in conjunction with aspirin?

Did I get the basics there? If so, that’s about the most incredible thing I’ve ever read, and would seem to align with just about everything I’ve learned/experienced so far.

Thanks in advance!
Yes that's my read, you have summed it up much more succinctly than I have.

Having relied on glucocorticoids and immunosuppressants in the past, for me it isn't as straight forward as:

- study shows x is anti-inflammatory = good, take more.
- study shows x is pro-inflammatory = bad, avoid it.

Inflammation is an intentional act by the body. Is some substance pro-inflammatory because it is outright poison, or could it be some other mechanism as shown above with aspirin.

The body intentionally regulates metabolism, we cannot apply a blanket statement saying that low metabolism is always bad and high is always good. For example in fasting, low metabolism is good in that it prevents catabolism from consuming you entirely, it is also bad for all the negatives we normally associate with having a low metabolism. You could also simultaneously have hypermetabolism and poor (cellular) health, as commonly seen in rapid weight loss due to illness. It seems like a similar process is happening here with the body's immune capacity, no good or bad, just adaptive.

When we intervene in this process we have to uphold this 'contract'. We can choose to inhibit some of the self-preservative measures the body has taken because we have the means to supply it with outside resources it cannot account for. However, if we inhibit measures simply because they cause undesirable symptoms and don't give anything back, then the contract is violated. For example, many bad reactions here with people forcing T3, also negative outcomes with aspirin.
 
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bigc

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Platelet-Activating Factor–Induced Reduction in Contact Hypersensitivity Responses Is Mediated by Mast Cells via Cyclooxygenase-2–Dependent Mechanisms (2018)

Context
Platelet-activating factor (PAF) is a phosphopilid that causes platelet aggregation. It is also mediator of inflammation and causes target cells to produce prostaglandins, cytokines, and other inflammatory mediators. This PAF receptor (PAFR) activation thus induces acute pro-inflammatory responses.

However it also modulates host immunity thereby inducing delayed systemic immunosuppressive effects. Mast cell (MC) PAFR activation induces MC-derived histamine and PGE2 release which are suggested to be involved in PAFR-induced immunosuppression.

PAF is tightly regulated as it mediates many intercullar interactions. Dysregulation, exogenous sources or oxidative stress can be a mechanism of disease. Oxidative stressors, such as UVB, chemotherapy, and cigarette smoke, can oxidise membrane phospholipids generating PAF and PAF-like molecules.

Mast cells are long-lived hematopoietic cells [blood cell production - haima (blood) and poiēsis (to produce something)] cells that initiate allergic responses upon recognition of pathogenic stimuli. MC activation release prepackaged inflammatory mediators such as histamine, seratonin and proteases. MC can also synthesise and secrete cytokines and chemokines.

Results
Using PAFR KO mice, MC PAFR activation was found to be necessary and sufficient to mediate PAFR-induced systemic immunosuppression. It was then shown that immunosuppression was defective in MC-deficient mice and MC-deficient mice transplanted with histidine-decarboxylase MC or cyclooxygenase-2-deficient (COX-2) MC.

It was shown that histidine-decarboxylase knockout (HDO) mice, lacking the enzyme responsible for histamine biosynthesis only exhibited immunosuppression in response to treatment with histamine. Thus, MC PAFR activation sufficiently drives immunosuppression via a histamine involved process.

Previous studies show that PAFR agonist–induced (e.g., UVB, cigarette smoke, and CPAF [carbamoyl PAF analog]) immunosuppression can be blocked by COX-2 inhibitors. In this study, COX-2 inhibitors blocked the immunosuppressive effects of both CPAF and histamine in mice. Furthermore, mice transplanted with COX-2 KO MCs also resisted immunosuppression. Thus, this demonstrates that COX-2 contributes to PAFR-induced immunosuppression.

The study further showed that MC migration to lymph nodes after PAFR activation is regulated by COX-2. MC migration to draining lymph nodes is necessary to mediate systemic immunosuppression. In the lymph nodes, MCs may induce systemic immunosuppression via production of cytokines such as TGF-β.

Altogether this suggests that COX-2 and histamine mediate PAFR-induced immunosuppression. A proposed mechanism for the involvement of COX-2 is that PGE2 has been previously implicated in regulating immune cell chemotaxis. Furthermore, histamine can promote prostaglandin release.

It appears that a pro-inflammatory threshold must be reached before subsequent immunosuppression ensues as MCs migrate to draining lymph nodes. COX-2 derived prostaglandins and histamine contribute to the pro-inflammatory threshold activation energy.



This expands on the 2015 study by the same group of researchers: Mast cell-derived histamine is necessary for platelet-activating factor mediated systemic immunosuppression (IRC4P.606) which has been covered on RPF previously.

Mast Cell-derived Histamine Is Necessary For Platelet-activating Factor Mediated Systemic Immunosupp
 

Lejeboca

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We have hypothesized that cellular exhaustion is related to suppression of the LPS response in sequential LPS treatments. Two pathways that relate to exhaustion are metabolism and the production of reactive oxygen species.

The paper below presents an additional effect on the excess (tolerance) on LPS:

These findings suggested that hepatic drug-metabolizing enzyme activity might be decreased by the administration of ITS, as the liver is usually considered to be the major organ for drug biotransformation. This expectation is supported by the results presented in Table II; UDP-glucuronyltransferase activity of the liver isolated from the LPS-administered rats was decreased significantly compared with the control. However, the enzyme activities of extrahepatic organs such as lung and kidney were also significantly affected.

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