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.
Highlights
The synergistic induction of IDO by IFN-γ and TNF-α occurs in primary murine microglia and, in vivo studies suggest that this synergy participates in the IDO-mediated generation of depressive-like behavior in mice inoculated with bacille Calmette-Guérin (BCG) (O’connor et al, 2009a), a model of inflammation-related depression (Moreau et al, 2008)
Mechanistic insights into the role of the kynurenine pathway in multiple sclerosis: lessons from the EAE model Since resident microglial activation and macrophage infiltration into the CNS are common features of both MS and EAE, initial interest in the role of KP metabolism in the pathogenesis of EAE arose from findings that cultured human macrophages can produce quinolinic acid (QUIN) at neurotoxic levels in response to acute treatment with IFN-γ (Heyes et al, 1992; Chiarugi et al, 2001a)
Potential therapeutic intervention by modulation of kynurenine pathway in multiple sclerosis The emerging model of KP metabolism in the underlying biology of EAE and potentially MS suggests that IDO activity, enhanced by IFN-γ released from pathogenic T-cells, may in turn serve to limit their survival and/or facilitate the expansion of immunoregulatory T-cell phenotypes during inflammation
Summary
The synergistic induction of IDO by IFN-γ and TNF-α occurs in primary murine microglia and, in vivo studies suggest that this synergy participates in the IDO-mediated generation of depressive-like behavior in mice inoculated with BCG (O’connor et al, 2009a), a model of inflammation-related depression (Moreau et al, 2008). Damage of mutant Htt expressing neurons is suggested to lead to microglia activation, which includes secretion of cytokines as well as increased IDO transcription and generation of neuroactive kynurenine metabolites (Schwarcz and Pellicciari, 2002).
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