Immune Influencers in Action: Metabolites and Enzymes of the Tryptophan-Kynurenine Metabolic Pathway

Abstract

The tryptophan (TRP)-kynurenine (KYN) metabolic pathway is a main player of TRP metabolism through which more than 95% of TRP is catabolized. The pathway is activated by acute and chronic immune responses leading to a wide range of illnesses including cancer, immune diseases, neurodegenerative diseases and psychiatric disorders. The presence of positive feedback loops facilitates amplifying the immune responses vice versa. The TRP-KYN pathway synthesizes multifarious metabolites including oxidants, antioxidants, neurotoxins, neuroprotectants and immunomodulators. The immunomodulators are known to facilitate the immune system towards a tolerogenic state, resulting in chronic low-grade inflammation (LGI) that is commonly present in obesity, poor nutrition, exposer to chemicals or allergens, prodromal stage of various illnesses and chronic diseases. KYN, kynurenic acid, xanthurenic acid and cinnabarinic acid are aryl hydrocarbon receptor ligands that serve as immunomodulators. Furthermore, TRP-KYN pathway enzymes are known to be activated by the stress hormone cortisol and inflammatory cytokines, and genotypic variants were observed to contribute to inflammation and thus various diseases. The tryptophan 2,3-dioxygenase, the indoleamine 2,3-dioxygenases and the kynurenine-3-monooxygenase are main enzymes in the pathway. This review article discusses the TRP-KYN pathway with special emphasis on its interaction with the immune system and the tolerogenic shift towards chronic LGI and overviews the major symptoms, pro- and anti-inflammatory cytokines and toxic and protective KYNs to explore the linkage between chronic LGI, KYNs, and major psychiatric disorders, including depressive disorder, bipolar disorder, substance use disorder, post-traumatic stress disorder, schizophrenia and autism spectrum disorder.

Keywords: autism spectrum disorder; bipolar disorder; chronic inflammation; depression; immune tolerance; inflammatory factor; kynurenic acid; kynurenine; low-grade inflammation; post-traumatic stress disorder; schizophrenia; substance use disorder.

Figure 1

Acute inflammation, chronic low-grade inflammation and the status of pro-inflammatory and anti-inflammatory factors. (a) Acute inflammation onsets with the increase of inflammatory factors and is resolved with the decrease of inflammatory cytokines (yellow line). Chronic low-grade inflammation (LGI) is characterized by a period of relatively low-level inflammatory factors that induce immune tolerance. Eventually, inflammatory factors increase, leading to inflammatory exacerbation and contributing to the pathogenesis of various diseases (red line). (b) Relative levels of pro-inflammatory (in red) and anti-inflammatory (in green) factors after the onset and before the resolution of acute inflammation, during LGI and at inflammatory exacerbation.

Figure 2

The tryptophan-kynurenine metabolic pathway and bioactive kynurenine metabolites. The pathway depends on the type of cells. In some cells some enzyme is missing, and thus, some metabolite is not produced. The kynurenine metabolites are multifarious molecules with various properties. The aryl hydrocarbon receptor (AhR) ligands are circled with a blue dotted line; toxic kynurenines (KYNs) are in red shade, and protective KYNs are in green shade [20].

Figure 3

Stimulators (red) and inhibitors (blue) of the tryptophan-kynurenine metabolic pathway. The tryptophan 2,3-dioxygenase (TDO) is stimulated by cortisol and 3-hydroxyanthranilic acid (3-HA) but inhibited by nicotinamide adenine dinucleotide (NADH) forming a negative feedback loop. The indoleamine 2,3-dioxygenases (IDOs) are stimulated by interferon (IFN)-β, IFN-γ, tumor necrosis factor (TNF)-α and lipopolysaccharide (LPS) but inhibited by IL-4, IL-10 and superoxide dismutase (SOD). Kynurenine 3-monooxygenase (KMO) is stimulated by IFN-1 β, IFN-6, TNF-α, oxygen molecule (O₂) but inhibited by IL-4, IL-10 and SOD. KMO is also inhibited by NADH forming another negative feedback loop.