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.
Highlights
Chronic low-grade inflammation (LGI) has been linked to the prodromal stage of a broad range of chronic illnesses such as cardiovascular, metabolic, immunologic, neurodegenerative- and psychiatric diseases [1]
Four meta-analyses of serum or plasma samples from bipolar disorder (BD) patients invariably reported significantly increased levels of tumor necrosis factor (TNF)-α and Soluble IL-2 receptor (sIL-2R); IL-4, IL-6, IL-1RA, sIL-6R and TNFR1 levels were significantly increased in two metaanalyses; IL-10 levels were significantly increased in one meta-analysis [123,134,135,136]
Meta-analyses reported that Autism Spectrum Disorder (ASD) children had higher anxiety levels than normally developing ones, that high-functioning ASD adolescents are at high risk of developing anxiety disorders, and that autism population showed higher prevalence of anxiety disorders, the highest being attention-deficit hyperactivity disorders, in decreasing orders, sleepwake disorders, disruptive, impulse-control and conduct disorders depressive disorders, obsessive-compulsive disorder BD and SCZ spectrum disorders [179,180] (Table 2)
Summary
Chronic low-grade inflammation (LGI) has been linked to the prodromal stage of a broad range of chronic illnesses such as cardiovascular-, metabolic-, immunologic-, neurodegenerative- and psychiatric diseases [1]. The long-term immune tolerance proceeds to significantly higher secretion of inflammatory factors which is linked to inflammatory exacerbation and pathogenesis of a wide range of neurologic- and psychiatric diseases [3] (Figure 1b). The tryptophan (TRP)-kynurenine (KYN) metabolic pathway is gaining growing attention as the immune regulator which plays a crucial role of the pathogenesis of a wide range of diseases from cancer to psychiatric disorders. The activation of immune system, and the TRP-KYN pathway were linked in the elderly as well as neurodegenerative diseases [12,13]. This review article discusses the metabolites and enzymes of the TRP-KYN metabolic pathway with a special emphasis on its interaction with the immune system, and the major symptoms, pro- and anti-inflammatory cytokines and toxic and protective KYNs of major psychiatric disorders
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