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.

Keywords: G-protein-coupled receptor 35; aryl hydrocarbon receptor; immunomodulation; inflammation; kynurenic acid; microbiota; tryptophan metabolism.

Figure 1

Kynurenic acid (KYNA) synthesis along the kynurenine pathway and its mode of action. The catabolism of TRP by the enzymes TDO or IDO represents the rate-limiting step in KYNA synthesis. The intermediate metabolite kynurenine can be further processed through three distinct pathways to form KYNA, 3-hydroxykynurenine, and anthranilic acid. KYNA is formed by the irreversible transamination of KYN either via kynurenine aminotransferases (KAT I–IV) or through the action of reactive oxygen species (ROS). KYNA is a non-competitive antagonist of ionotropic glutamate receptors (GLUT-R) as well as of the α7 nicotinic acetylcholine receptor (α7nAChR) expressed on neuronal cells. Apart from neuromodulatory properties, KYNA is an agonist of the broadly expressed G-protein-coupled receptor 35 (GPR35) and aryl hydrocarbon receptor (AhR). Furthermore, KYNA functions as an ROS scavenger. Black arrows mark enzymatic reactions and dashed arrows include more than one catalytic reaction step. FOR, formamidase; IDO, indolamine 2,3-dioxygenase; TDO, tryptophan 2,3-dioxygenase; TPH, tryptophan hydroxylase; KAT, kynurenine aminotransferase; KMO, kynurenine 3-monooxygenase; KYN, kynureninase; AMO, anthranilate 3-monooxygenase; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; NMDA, N-methyl-D-aspartate receptor; KAR, kainate receptor.

Figure 2

Kynurenic acid (KYNA)-mediated pathways of inflammatory signaling. Pro-inflammatory cytokines induce the expression of indolamine (IDO) enzyme via STAT, AP1, IRF1, and NF-κB transcription factor activation. KYNA is formed by the IDO-dependent canonical pathway or by an alternative route through direct kynurenine (KYN) or tryptophan (TRP) transformation by reactive oxygen species (ROS). On the other hand, KYNA as a free radical scavenger decreases ROS level. KYNA binds and activates G-protein-coupled receptor 35 (GPR35)-reducing cAMP and calcium (Ca²⁺) levels in cells. Activation of GPR35 by KYNA may also inhibit phosphorylation of protein kinase B (AKT), extracellular signal-regulated kinase (ERK), and p38 mitogen-activated protein kinase (p38), as well as increasing the level of β-catenin. All of these cellular responses probably decrease activation of relevant inflammatory transcription factors, such as NF-κB and AP1. Therefore, reduced induction of tumor necrosis factor α (TNF), high-mobility group box 1 (HMBG1), interleukin 4 (IL4), α defensin (α-Def), and inducible nitric oxide synthase (iNOS) have frequently been observed in response to KYNA treatment. Recruitment of arrestin β2 (ARRB2) to GPR35 is necessary for internalization and desensitization of the KYNA-activated receptor. Binding of KYNA to the aryl hydrocarbon receptor (AhR) receptor leads to recruitment of the AHR nuclear translocator (ARNT) and induction of IL6 expression. Interaction of the KYNA–AhR complex with NF-κB may also be involved in the induction of IL6. Furthermore, ligand-activated AhR initiates the proto-oncogene tyrosine-protein kinase Src activation and, thereby, the phosphorylation (P) of IDO. Phosphorylated IDO induces the expression of transforming growth factor β1 (TGFβ). NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells; AP1, activator protein 1; STAT, signal transducer and activator of transcription; IRF, interferon-regulatory factor; G, G protein.