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Pathway Description
Anti-inflammatory pathway
Homo sapiens
Disease Pathway
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.
References
Anti-inflammatory pathway References
Bello C, Heinisch PP, Mihalj M, Carrel T, Luedi MM. Indoleamine-2,3-Dioxygenase as a
Perioperative Marker of the Immune System. Front Physiol 2021; 12:766511.
Herrera-Van Oostdam AS, Castañeda-Delgado JE, Oropeza-Valdez JJ, et al. Immunometabolic
signatures predict risk of progression to sepsis in COVID-19. PLoS One 2021; 16(8): e0256784.
Guarnieri T. Hypothesis: Emerging Roles for Aryl Hydrocarbon Receptor in Orchestrating CoV-
2-Related Inflammation. Cells 2022; 11(4): 648.
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