Chronic Danger and the Inflammatory-Immunosuppressed State

Explored through the context of Type 1 Diabetes

3/19/2020

The exposure of hydrophobic materials into the blood or interstitium alerts the immune system to the presence of danger in the form of microbial infection or cellular damage[1]. Replicating or ruptured microbes release hydrophobic materials called pathogen-associated molecular patterns (PAMPs). Similarly, stressed or damaged host cells expose hydrophobic contents called damage-associated molecular patterns (DAMPs) that are normally hidden in healthy cells. These hydrophobic signals act through the pattern recognition receptors (PPRs) expressed on immune cells to initiate a protective immune response to infection or injury, but the presence of extracellular hydrophobicity itself is a danger to the organism[1]. Hydrophobicity in the extracellular fluids is protected against in various ways in order to prevent hydrophobic aggregates/micelles from developing and disrupting tissues[1]. Hydrophobic materials from dietary lipids or damaged host and bacterial cells are scavenged by humoral quenchers, such as apolipoproteins, lipid-transfer protein (LTP), lipopolysaccharide-binding protein (LBP), chylomicrons, LDLs, and HDLs[1][2]. When the concentration of these materials overwhelms the capacity of quenching-agents to scavenge them, they will stimulate PRRs.
Lipoprotein Lipase (LPL), expressed on the endothelial cells of capillaries, breaks down triglycerides in chylomicrons and LDL particles into free fatty acids (FFAs) that are then absorbed and metabolized by heart and skeletal muscle cells or stored in adipose tissue. When the supply of FFAs exceeds the capacity for metabolism or storage, the FFAs released by LPL spill over and continue flowing downstream in their unesterified form[3], mostly bound to albumin[4]. High levels of FFAs interfere with insulin[5] and thyroid hormone sensitivity[6] and can cause lipotoxicity-induced apoptosis of various tissues, including the pancreatic ß cells[7]. Albumin protects against much of the toxicity of FFAs and the declining ratio of albumin to FFAs, as is seen with aging, allows for FFAs to roam unbound and is a predictor of coronary heart disease[8]. FFAs trigger the toll-like-receptors (TLRs) class of PRRs, TLR2 and TLR4[9].
Stress promotes the exposure of hydrophobicity in various ways. Hormone Sensitive Lipase (HSL), which liberates FFAs from adipose cells, is stimulated by the stress mediating hormones adrenaline, glucagon, and ACTH, and is inhibited by insulin. Cellular stress, such as a lack of oxygen or glucose supply, and necrotic death cause the release of DAMPs[10]. Adrenaline shifts the blood away from the intestine causing the intestinal membrane to lose tone and leak more of the bacterial PAMP, lipopolysaccharide (LPS, endotoxin), into the blood[11]. The increased exposure to hydrophobic materials during stress activates inflammatory processes as a protective mechanism, but prolonged stress and exposure to hydrophobicity leads to degenerative changes.
Acute activation of innate cell PRRs by their hydrophobic ligands activates transcription factors that lead to the production of various pro-inflammatory mediators. For example, acute signaling of LPS through the TLR4 receptor on macrophages and dendritic cells stimulates the release of TNFα, IL-1, IL-6, IL-12, Type 1 IFNs[12], leukotrienes, prostaglandins, nitric oxide (NO)[13][14], and chemokines. In both mice and humans injected with LPS, TNFα, IL-6, and chemokines peak at 2 hours after injection and return to baseline by 6 hours[15]. LPS activation of macrophages and dendrites causes a shift in the metabolism to glycolysis[16], supporting a cellular shift towards a reductive state. Macrophages and dentrites with a high GSH/GSSG ratio are known to support a Th1 polarization of CD4 T cells. GSH is known to support IL-12 production by macrophages[17]. IL-12 and Type 1 IFNs are the key signals that drive the Th1 polarization (IFN𝛾) of CD4 T cells [18][12] and the production IFN𝛾 from NK and NKT cells. In LPS challenged mice, splenic IL-12 production peaks between 4-6 hours and then IFN𝛾 production peaks at 8 hours, with NK (60%) and NKT (25%) cells representing the major sources, and T cells, macrophages and dendritic cells accounting for the rest[19]. 10 minutes after LPS treatment NO is generated from constitutive endothelial NO synthase (eNOs) and reaches a peak at 30 minutes, followed by a return to baseline[20]. At 1 hour, NO again begins to increase gradually due to production from inducible NO synthase (iNOs). TLR4 signaling is an essential promoter of COX2 activation[21]. Plasma concentrations of prostaglandin E2 (PGE2) begin to increase at 2 hours after LPS challenge[22].
In the event of sepsis, which is caused by extreme PRR signaling, and is most often driven by LPS[23][24], the innate system responds with a dramatic production of the above mentioned pro-inflammatory mediators. This was originally considered to drive the negative outcomes of sepsis. However, in the mid-90s, after the failure of immunosuppressive drugs to successfully treat septic patients and the discovery of both pro-inflammatory and anti-inflammatory mediators in septic patients, termed “immune dissonance”, the causes of fatal sepsis were reevaluated[25]. It is now known that a distinct anti-inflammatory profile follows the initial pro-inflammatory burst and it is the extent of this anti-inflammatory response, as detected by reduced IFN𝛾[26] and higher IL-10 and IL-4, indicative of TH2 skewing, that best predicts mortality in sepsis [27][28][29]. This is called the compensatory anti-inflammatory response syndrome (CARS)[26], and although pro-inflammatory cytokines may in some cases still be generated above baseline (dissonance), the anti-inflammatory system dominates.
Prolonged signaling of any PRR causes general PRR tolerance. Regardless of which PRR class is being over-stimulated, all receptors show down-regulated triggering of pro-inflammatory behavior[30]. Under prolonged LPS signaling, macrophages and dendrites develop an anti-inflammatory cytokine profile of IL-4 and IL-10, show reduced HLA-DR expression[31] and phagocytosis [26], and stimulate Th2 differentiation. This phenotype is termed “endotoxin tolerance”. While inflammatory cytokines are reduced, the innate cells continue to produce inflammatory PGE2 and NO [32][33][34]. Therefore, while endotoxin tolerance was originally considered a paralysis of the immune system to respond to LPS, it actually represents an alternate activation that triggers unique behavior [30], not to be confused with the anti-inflammatory M2 polarization of macrophages that does not include excessive PGE2 and NO production[35]. PGE2 largely drives the attenuated pro-inflammatory response in innate cells[36]. Together, PGE2 and NO have overlapping effects, directly causing inflammation, suppressing innate and adaptive immunity, and both contributing to unregulated tissue growth and degeneration[37][38]. Endotoxin tolerance can be substantially induced after 6-8 hours of exposure to LPS and lasts up to 5 days[39].
Within 24 hours of the onset of sepsis, the immunosuppressive state (CARS) sets in [28]. Various immunosuppressive mediators drive this refractory state. IL-10, PGE2, NO, increased myeloid-derived suppressor cells, and increased corticosteroids are suspected as the major drivers of the immunosuppression[28][40][41]. These factors combine to cause lymphopenia, the impairment of CD4 and CD8 T cells, NK cells, and B cell-mediated immunity, and an increase in regulatory T cells[40][42]. NO may itself cause the main manifestations of septic shock, by decreasing blood pressure and blood delivery to tissues, causing organ damage[43]. Immunosuppression also leads to a tendency towards secondary or worsening of infection. IFN𝛾 has been seen to reverse immunosuppression in sepsis [44].
During sepsis, further hydrophobic burden comes from an increased mobilization of FFAs[45] and from increased DAMPs released by stressed tissues[46][47].
The worst consequences of immunosuppression are generally considered to be the vulnerability towards infection, but when the immune system is viewed from the perspective of Jamie Cunliffe’s morphostatic system, the derangement of the immune system would have more direct consequences. The immune system, or morphostatic system, is constantly maintaining healthy tissue morphological stasis, and its impairment would lead to irregular growth or degeneration of organ tissues[48]. In Type 1 diabetes, for example, cachexia, the wasting of muscle tissue, has been specifically linked to lymphopenia[49].
The inflammatory-immunosuppressed state does not only arise from the prolonged exposure to extremely high LPS, as is seen in sepsis, but also occurs in a proportionally less severe and chronic manner in more moderate, chronic endotoxemia. In patients with liver cirrhosis, pancreatitis, and cystic fibrosis[30], chronic endotoxemia produces similar immunological changes to the CARS in sepsis[31].
In short bursts, LPS and other PRR agonists activate an acute inflammatory immune response [15], and in NOD mice, where immunodeficiency is a necessary component of their diabetes development, this response can have protective effects. For example, treatments with various TLR agonists, especially TLR2, which is known to trigger the autoimmune reaction to ß cell necrosis, were seen to prevent or delay diabetes[50]. A peritoneal injection of bacterial extract completely prevented diabetes in NOD mice in a TLR2 and TLR4 dependent fashion[51]. LPS injected once had a temporary beneficial effect on blood glucose but injected once per week for 4 weeks reduced the incidence of diabetes by 75% without reducing the degree of inflammation in the islets[52].
Since inducing endotoxin tolerance requires constant stimulation for 6-8 hours and only lasts up to 5 days, and since LPS is quickly removed from the system, once-weekly injections of LPS do not represent a proper model of chronic endotoxemia and endotoxin tolerance, and instead act as intermittent immunostimulatory events. One study claimed to delay diabetes onset and reduce diabetes incidence in NOD mice by inducing endotoxin tolerance with once-weekly E. coli LPS injections[53]. Caramalho et al. performed a similar experiment, injecting 10 μg of LPS from E. coli into NOD mice once weekly, with a similar success of preventing diabetes [54]. However, mice were also analyzed for immunological activity. Mice that were protected against diabetes showed increased lymphocyte number and activity in the spleen and pancreatic lymph nodes, sustained insulitis scores, and infiltration of CD4+IFN𝛾+ to the pancreas. The authors explained that the treatment does not cause immune paralysis, therefore, it is not representative of an endotoxin tolerant state. Mice treated with the same dosage every 3 days were not robustly protected against diabetes, except for a delay in onset. More frequent dosing is more likely to induce an endotoxin tolerant state. Unfortunately, there is a paucity of literature discussing the effects of chronic endotoxemia induced immunosuppression on diabetes outcomes in animal models. In one study with autoimmune diabetes-prone BB rats (DPBB), LPS in the feed caused the incidence of diabetes to rise from 50% to 75%[55]. The LPS fed rats showed a significant decrease in IFN𝛾 gene expression but not in that of TGFß.

Type 1 diabetics of at least 2 years duration show a fasting endotoxin of 592.5% higher than healthy controls and of 982.49% at onset[56]. An increase in intestinal permeability is seen before the clinical onset of diabetes in both humans and the DPBB rat[57]. Type 1 diabetics have an increased risk of sepsis and 100% of untreated diabetic mice die from sepsis, compared to 50% of non-diabetic mice, and show complete lack of pre-lethal inflammatory cytokine response[58][59]. Monocytes isolated from Type 1 diabetic females showed a reduced response of inflammatory cytokines (TNFα, IL-1, and IL-6) to LPS compared to non-diabetic controls, yet do not show suppressed IL-10 production[60], suggestive of an endotoxin tolerance state. The same pattern of endotoxin tolerance is apparent in Type 2 diabetics[61]. Type 1 diabetes onset is best predicted by raised anti-inflammatory cytokine IL-10 levels, not the inflammatory cytokines[62]. Monocyte Cox-2 levels and plasma PGE2 levels are chronically elevated in Type 1 diabetics[63]. NO is also chronically elevated[64]. These patterns support that Type 1 diabetics are in an endotoxin tolerant, inflammatory, immunosuppressed state, inhibiting the protective Th1 autoimmunity that has been explored in previous articles[65][66].
There are many articles discussing chronic endotoxemia in Type 1 diabetes, but very few mention the involvement of endotoxin tolerance, even though it is the natural outcome of chronic endotoxemia. Where it is mentioned, it is suggested to be a protective state, since endotoxin tolerance is potently immunosuppressive and immunosuppression is believed to protect against autoimmune diabetes. Studies claiming to show the protective potential of endotoxin tolerance fail to induce endotoxin tolerance. Endotoxin tolerance seems to be more openly discussed as a pathological feature in Type 2 diabetes, which is not considered an autoimmune disease.
Chronic endotoxemia may be a key factor in ß cell destruction. ß cells express the TLR4 receptor. In response to TLR4 ligation by LPS for 48 hours, ß cells show reduced insulin content and secretion[67]. LPS may also indirectly damage ß cells by its stimulation of NO and PGE2, which are both notably elevated in Type 1 diabetics and are directly toxic to ß cells[68][69][70][71][72]. Further, the impairment of the Th1 adaptive immune response, which activates progenitor ß cells and sustains the tissue morphology of the pancreas, will reduce the ability of the ß cells to regenerate after damage.
Enhanced gut permeability to lactulose is consistently seen in preclinical, new-onset, and long-term Type 1 diabetics, indicating that the enteropathy is not secondary to hypoinsulinemia nor treatable by insulin therapy[57]. Similarly, in the DP-BB rat, high gut permeability is a consistent feature and is present before insulitis[73]. NOD mice with restricted gut bacteria, without gram-negative strains, and hence no LPS, are protected from diabetes[74]. Various antibiotics have protected DP-BB rats and NOD mice from diabetes[73][75]. Blockage of the TLR4 receptor prevents diabetes in NOD mice[76].
Flu often precedes new-onset cases of Type 1 diabetes. Gut permeability is enhanced during influenza[77]. PGE2 is the major driver of fever[78] and NO is elevated during influenza infection[79]. Prior psychological trauma is also seen to increase the likelihood of developing Type 1 diabetes by a factor of three[80]. Psychological distress enhances gut permeability[81].
Once hypoinsulinemia occurs, the increased lipolysis of FFAs[82] adds to the hydrophobic burden of increased LPS. Rapid cachexia, driven by excess glucagon[83], cortisol and lack of insulin[84], and cellular stress, caused by insulin deficiency and elevated stress mediators, raises the exposure of hydrophobic DAMPs. DAMPs such as heat shock protein 60 (HSP60) and high mobility group box 1 (HMGB1) are seen to increase alongside LPS in Type 1 diabetics[85]. Since endotoxin tolerance can be triggered through chronic signaling of any class of PRR, the multiple contributors to hydrophobicity ensure immunosuppression and the continued release of PGE2 and NO. Raising levels of free polyunsaturated fatty acids (PUFA), and in particular arachidonic acid, which are preferentially released by HSL[86], increase the available substrate for PGE2 synthesis by COX-2. Muscle cachexia releases glutamine and arginine, supporting enhanced NO production[87]. Cells exposed to excessive PUFA also show increased leakiness[88][89][90][91][92][93], likely contributing to the loss of the gut barrier, loss of blood volume, and increased exposure of DAMPs. Mice made deficient in PUFA are resistant to endotoxin-induced increases in vascular permeability[94], are resistant to endotoxic shock[95], and are resistant to multiple-low-dose streptozotocin-induced (MLD-STZ) diabetes[96]. PUFA deficient NOD mice have a diabetes incidence of 20%, compared to 68.75% in controls[97]. Endotoxin, collaborating with PUFA, is a likely cause of the vascular abnormalities seen in Type 1 diabetics[98][99].
COX-2 inhibition prevents MLD-STZ induced diabetes[100] and improves glucose stimulated insulin secretion in hyperglycemic mice[101]. iNOs inhibition normalizes glycemia and improves insulin secretion in prediabetic NOD mice[102] and reduces hyperglycemia in MLD-STZ mice[103]. eNOS inhibition significantly reduces incidence of diabetes in DP-BB rats[104].
The mistake of treating sepsis as an overactive inflammatory immune disease has been acknowledged. A similar mistake has been made in the approach towards Type 1 diabetes, and likely numerous other diseases with underlying chronic endotoxemia. The contradictory evidence for diabetes protection from both TLR4 stimulation and TLR4 inhibition shows the complexity of the immune response to danger. Acute stimulation activates the protective innate and adaptive inflammatory system that repairs tissue, but chronic activation leads to the alternative activation of the immunosuppressive-inflammatory state. Blockade of TLRs may prove protective via the prevention of endotoxin tolerance. However, TLRs are the fundamental sensor to danger and are required to mount a protective autoimmune response to ß cell damage and future infections. Although TLR blockers could have benefit, the potential problem of deafening the immune system to danger seems a worse option than resolving the more fundamental problem of excess LPS and other hydrophobic signals. Managing the gut biome and permeability and preventing dyslipidemia with antilipolytic agents represent a more robust response.
Endotoxemia appears to be a general component of stress and disease. Endotoxin tolerance, the quiescence of the immune system, may be a common factor that impairs the ability to heal from organ injury, leading to chronic disease. The immune system, as the morphostatic system, must be enabled to support healing. Mice that are kept in a germ-free environment heal without any scarring[105]. Certain antibiotics may be beneficial by reducing bacterial count and improving gut permeability[106]. Casein is seen to repair the gut lining and protect against diabetes[107]. Aspirin[108] and methylene blue[109] respectively reduce the PGE2 and NO profile of endotoxin tolerance, and aspirin prevents adrenaline-induced lipolysis[110]. Vitamin D reverses endotoxin tolerance[111] and protects against gut dysbiosis and permeability[112]. These substances have potential merit in Type 1 diabetes. Sufficient insulin treatment to reduce lipolysis can be paired with a moderated fat intake to prevent FFA spillover and an over-sufficient carbohydrate intake to maintain slight hyperglycemia as an incentive for ß cell regeneration[113], a subject that will be investigated in future articles.


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