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.

Maternal Immune Activation Causes Social Behavior Deficits and Hypomyelination in Male Rat Offspring with an Autism-Like Microbiota Profile

“…The elevated levels of inflammatory cytokine (TNF-α and IL-1β) in the gestational stage are associated with behavioral impairment and hypomyelination [34,37]. The activation of an inflammatory reaction, including pro-inflammatory and anti-inflammatory cytokines, is associated with ASD [38][39][40][41]. In addition, poly I:C-induced MIA increases TNF-α and IL-1β expression in the colon of MIA offspring with an altered microbiota profile [42].…”

Co-Players in Chronic Pain: Neuroinflammation and the Tryptophan-Kynurenine Metabolic Pathway

“…Inflammation is invariably linked to the activation of TRP metabolism [ 27 , 28 ]. The essential amino acid TRP is a precursor to serotonin, melatonin, and nicotinamide adenine dinucleotide (NAD + ), among others.…”

“…Inflammation activates the TRP–KYN pathway, elevating the levels of oxidative compounds or neurotoxic ligands to receptors of the excitatory glutamatergic nervous system, which damage the peripheral nervous system or CNS through the broken blood–nerve or blood–brain barrier, respectively [ 16 ]. Furthermore, immunomodulators are known to trigger the shift of acute inflammatory status toward tolerogenic and chronic inflammation, perpetuating low-grade inflammation [ 28 , 37 ]. KYN is synthesized from TRP by the tryptophan 2,3-dioxygenase (TDO) in the liver and the indoleamine 2,3-dioxygenases (IDOs) in the brain and the immune system, which are induced by cortisol, and interferon (IFN)-α, IFN-γ, and tumor necrosis factor (TNF)-α, respectively [ 38 ].…”

A Biopsychosocial Approach to Grief, Depression, and the Role of Emotional Regulation

“…Recent literature has explored different biomarkers that could be linked to inflammation, and their association with chronic psychological disorders [ 90 ]. This section will discuss recent literature that suggests that loss could lead to psychopathology, while at the same time having an impact at the physiological level.…”