Kynurenic Acid: The Janus-Faced Role of an Immunomodulatory Tryptophan Metabolite and Its Link to Pathological Conditions

Abstract

Tryptophan metabolites are known to participate in the regulation of many cells of the immune system and are involved in various immune-mediated diseases and disorders. Kynurenic acid (KYNA) is a product of one branch of the kynurenine pathway of tryptophan metabolism. The influence of KYNA on important neurophysiological and neuropathological processes has been comprehensively documented. In recent years, the link of KYNA to the immune system, inflammation, and cancer has become more apparent. Given this connection, the anti-inflammatory and immunosuppressive functions of KYNA are of particular interest. These characteristics might allow KYNA to act as a “double-edged sword.” The metabolite contributes to both the resolution of inflammation and the establishment of an immunosuppressive environment, which, for instance, allows for tumor immune escape. Our review provides a comprehensive update of the significant biological functions of KYNA and focuses on its immunomodulatory properties by signaling via G-protein-coupled receptor 35 (GPR35)- and aryl hydrocarbon receptor-mediated pathways. Furthermore, we discuss the role of KYNA–GPR35 interaction and microbiota associated KYNA metabolism for gut homeostasis.

Immune and Neuroendocrine Trait and State Markers in Psychotic Illness: Decreased Kynurenines Marking Psychotic Exacerbations

“…Similar to a mechanism proposed in glioblastoma patients, in whom plasma concentrations of Trp, Kyn, KA, and QA were found to be decreased compared with healthy controls in the context of CNS IDO1 upregulation (47), decreased peripheral KA could be indicative of an increased demand for and transfer of Trp or Kyn through the blood-brain barrier to serve as substrate for local synthesis of KA in brain tissue. This corresponds to increased KA concentrations in the CSF of patients with schizophrenia (48). This hypothesis however does not explain why KA remains decreased throughout the illness course as trait marker while, especially in younger patients, 3-HK and QA concentrations increase post-treatment.…”

Orchestration of Tryptophan‐Kynurenine Pathway, Acute Decompensation, and Acute‐on‐Chronic Liver Failure in Cirrhosis

“…However, in the setting of SI there is intense overexpression of IDO and extrahepatic production of Trp‐KYN derivatives including kynurenine (KYN, which is an endothelial‐derived relaxing factor and neuroactive molecule), quinolinic acid (QA, which is a neuronal N ‐methyl‐ d ‐aspartic acid [NMDA] receptor neurotoxic agonist), and kynurenic acid (KA, which is a NMDA antagonist). KYN and KA exert immunomodulatory actions by binding to aryl hydrocarbon receptor and GPR35 in immune cells . In addition, the KP can produce picolinic acid (a second NMDA receptor antagonist), as well as the immunosuppressive metabolites 3‐hydroxykynurenine (3‐HK) and 3‐hydroxyanthranilic acid (3‐HAA) .…”

“…KYN and KA exert immunomodulatory actions by binding to aryl hydrocarbon receptor and GPR35 in immune cells. (9,10) In addition, the KP can produce picolinic acid (a second NMDA receptor antagonist), as well as the immunosuppressive metabolites 3-hydroxykynurenine (3-HK) and 3-hydroxyanthranilic acid (3-HAA). (7)(8)(9) Finally, during KP activation, there is increased generation of highly reactive oxygen and nitrogen species, which contribute to immunopathology.…”

Are Kynurenines Accomplices or Principal Villains in Dementia? Maintenance of Kynurenine Metabolism

“…In addition, KYNA and XA are endogenous human AhR ligands. KYN, KYNA, and XA direct the adaptive immunity toward immune suppression [89].…”

“…Secondly, KYNA has been observed to have anti-inflammatory actions under inflammatory conditions. KYNA reduces TNF expression and secretion, diminishes high-mobility group box 1 protein secretion, inhibits α-defensin human neutrophil peptides 1-3 secretion, reduces IL-4 release in invariant natural killer-like T cells, reduces lipopolysaccharide-induced IL23 expression of dendritic cells, and inhibits Th17 cell differentiation in vitro [89].…”