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.

Kynurenine pathway metabolism and the microbiota-gut-brain axis

“…As noted above, kynurenine pathway metabolism is tightly regulated by inflammatory mediators and multiple enzymes in the pathway are immunoresponsive (Campbell et al, 2014). The gut microbiota engages dynamically with the host across the lifespan to educate and regulate the immune system (El Aidy et al, 2015;Round and Mazmanian, 2009).…”

The Kynurenine Pathway: A Primary Resistance Mechanism in Patients with Glioblastoma

“…increased secretion of pro-inflammatory cytokines plays a particularly important role in GBM development and resistance to therapy (74)(75)(76)). An important mechanism by which these cytokines cause and worsen these diseases is through of the kynurenine pathway (77)(78)(79)(80). campbell et al showed that iFNγ activates the kynurenine pathway, and TNFα, iL1β and iL6 are synergistic with iFNγ in stimulating this pathway (77).…”

“…An important mechanism by which these cytokines cause and worsen these diseases is through of the kynurenine pathway (77)(78)(79)(80). campbell et al showed that iFNγ activates the kynurenine pathway, and TNFα, iL1β and iL6 are synergistic with iFNγ in stimulating this pathway (77). Asp et al emphasized the important role of iFNγ in stimulating this pathway in dermal fibroblasts (78).…”

N-3 PUFAs and neuroinflammatory processes in cognitive disorders

“…serotonin, dopamine) and neuronal survival (Capuron and Miller, 2011;Dantzer et al, 2008). Indeed, increased brain or cerebrospinal fluid concentrations of kynurenine and its neurotoxic metabolites have been reported in several neurodegenerative and psychiatric disorders (Campbell et al, 2014; suggesting that IDO activation may lead to both functional and structural alterations in the brain. Consistent with this statement, activation of the kynurenine pathway has been recently reported to affect human neurogenesis in the hippocampal formation (Zunszain et al, 2012), an important brain structure involved in cognitive functions and an important site for IDO production (Andre et al, 2008;Frenois et al, 2007).…”