Kynurenines in CNS disease: regulation by inflammatory cytokines

Abstract

The kynurenine pathway (KP) metabolizes the essential amino acid tryptophan and generates a number of neuroactive metabolites collectively called the kynurenines. Segregated into at least two distinct branches, often termed the "neurotoxic" and "neuroprotective" arms of the KP, they are regulated by the two enzymes kynurenine 3-monooxygenase and kynurenine aminotransferase, respectively. Interestingly, several enzymes in the pathway are under tight control of inflammatory mediators. Recent years have seen a tremendous increase in our understanding of neuroinflammation in CNS disease. This review will focus on the regulation of the KP by inflammatory mediators as it pertains to neurodegenerative and psychiatric disorders.

Keywords: CNS disease; IDO; KAT; KMO; astrocytes; kynurenine; microglia; neuroinflammation.

Figure 1

Schematic representation of the kynurenine metabolic pathway. The kynurenine pathway is commonly segregated into two distinct branches that are regulated by KATs and KMO, as well as the availability of l-kynurenine within the brain. Additionally, kynurenine metabolism is regulated by a variety of proinflammatory mediators which impact enzyme expression levels, thereby altering substrate availability and metabolite formation favoring the KMO branch of the pathway under immune-related pathological conditions. TRP, tryptophan; 5-HT, serotonin; Kyn, kynurenine; KYNA, kynurenine acid; 3-HK, 3-hydroxykynurenine; AA, anthranilic acid; XA, xanthurenic acid; 3-HAA, 3-hydroxyanthranilic acid; QUIN, quinolinic acid; IDO, indoleamine-2,3-dioxygenase; KAT, kynurenine aminotransferase; KMO, kynurenine 3-monooxygenase; KYNU, kynureninase; HAAO, 3-hydroxyanthranilic acid oxidase; LPS, lipopolysaccharide; BCG, bacillus Calmette-Guerin; IFNs, interferons; TNF, tumor necrosis factor; IL, interleukin.

Figure 2

Regulation of IDO1 transcription by inflammatory signaling. IFN-γ-dependent IDO1 induction (middle). Canonical IFN-γ receptor signal transduction leads to (1) NF-κB- and STAT-1-dependent transcription of IRF-1, and (2) IRF-1- and STAT-1-dependent transcription of IDO1. Synergistic IDO1 induction (Left). IL-1β, LPS, and TNF-α enhance transcription of IFN-γ receptor in an NF-κB-dependent manner. TNF-α has been shown to synergistically enhance IFN-γ-dependent IDO1 transcription by promoting NF-κB- and STAT-1-dependent IRF-1 transcription (within dashed circle). IFN-γ-Independent IDO induction (Right). TLR4 stimulation by LPS leads to transcription of IDO1 by a mechanism that requires NF-κB and either p38 or JNK, but not IFN-γ. The 5′-flanking region of INDO, the gene encoding IDO1, contains two IFN-γ-activated sites (GAS) and two interferon-sensitive response elements (ISREs). One of the two GAS sequences and both ISRE sequences are required for IFN-γ-mediated IDO1 induction. The 5′ flanking region of INDO also contains at least one NF-κB binding site and several AP-1 binding sites, which may be required for IFN-γ-independent mechanisms of IDO1 transcription.