As the bacteria are cleared, tryptophan levels continue to drop as the indole dioxygenase (IDO) enzyme becomes more active. IDO activation results in the generation (from tryptophan) of kynurenine (and its other metabolites) through a self-stimulating autocrine process. Kynurenine binds to the arylhydrocarbon receptor (AhR) found in most immune cells [5-7]. In addition to increased kynurenine production via IDO mediated synthesis, hyopalbuminemia can also lead to the release of bound kynurenine (and other immunosuppressive LysoPCs) into the bloodstream to fuel this kynurenine-mediated immunosuppression process. Regardless of the source of kynurenine, the kynurenine-bound AhR will migrate to the nucleus to bind to NF-kB which leads to more production of the IDO enzyme, which leads to more production of kynureneine and more loss of tryptophan. High kynurenine levels and low tryptophan levels leads to a shift in T-cell differentiation from a TH1 response (pro-inflammatory) to the production of Treg cells and an anti-inflammatory response [5-7]. This often marks the beginning of the body’s return to normal and the impending end of the bacterial infection. High kynurenine levels also lead to the production of more IL10R (the interluekin-10 receptor) via binding of kynurenine to the arylhydrocarbon receptor (AhR). Activated AhR effectively increases the anti-inflammatory response from interleukin 10 (an anti-inflammatory cytokine). Low tryptophan levels also lead to the activation of the general control non-depressible 2 kinase (GCN2K) pathway, which inhibits the mammalian target of rapamycin (mTOR), and protein kinase C signaling. This leads to T cell autophagy and anergy. High levels of kynurenine also lead to the inhibition of T cell proliferation through induction of T cell apoptosis [5-7]. After bacterial clearance, the anti-inflammatory pathway is further activated and the pro-inflammatory process further deactivated. With the bacteria cleared, the production of pro-inflammatory cytokines are reduced due to lack of activity from TLR4 and other TLR stimulation. Additionally, anti-inflammatory cytokines (IL-10 and IL-4) are induced leading to a shift in the T-cells from a pro-inflammatory TH1 response to an anti-inflammatory Treg response. Likewise, with this T-cell shift, levels of cortisol and epinephrine drop, as do levels of glucose and NO. Blood pressure begins to rise to normal. Kynurenine levels fall due to continued kynurenine metabolism and uptake by serum albumin. More tryptophan is released or produced to arrest the IDO synthesis (which reduces kynurenine levels) which further reduces activation of the arylhydrocarbon receptor (AhR) which leads to the de-activation of the NF-κB pathway, which leads to lower levels of pro-inflammatory cytokines. Itaconate, accumulated by pro-inflammatory B-cells and T-cells, promotes the post-transcriptional modification of KEAP1, which induces the expression of the antioxidant response and PPARγ. PPARγ inhibits the NF-κB pathway and induces the expression of anti-inflammatory genes while at the same time increasing fatty-acid β-oxidation and glutaminolysis. Glutamine and fatty acids fuel the TCA cycle to support oxidative-phosphorylation. Aerobic glycolysis stops. The accumulated lactate and α-Ketoglutarate promote cysteine modifications that induce the expression of anti-inflammatory genes. Lactate levels in the blood drop as do glucose levels. Macrophages and other T-cells and B-cells begin to die or apoptose, the number of white blood cells drops and the body returns to normal.

Anti-inflammatory pathway References