Nat Rev Immunol 2016; 16(10): 626C638. and aging, and in so doing potentially increasing T863 the risk of developing psychiatric disorders. Novel therapeutic approaches targeting the KP are discussed. Moreover, electroconvulsive therapy, ketamine, physical exercise, and certain non-steroidal anti-inflammatories have been shown to alter kynurenine metabolism, raising the possibility that kynurenine metabolites may have power as treatment response or therapeutic monitoring biomarkers. 1.?OVERVIEW The kynurenine pathway (KP) is best known for its link with inflammatory disease. However, many of its metabolites, collectively termed kynurenines, are physiologically active and not only play a T863 key immunoregulatory role, but affect diverse physiological systems. Unlike other reviews which have generally focused on one particular sphere of influence or disorder, this review provides an overview of the impact of the kynurenines on several physiological pathways and symptom domains. In so doing, it highlights T863 the importance of the KP to the field of psychiatry, not only in terms of enhancing our mechanistic understanding of pathophysiology, but with respect to current and future therapeutic interventions. While the focus on psychiatric illness is intended to be wide-ranging, by necessity, the depressive disorder and schizophrenia literature is usually emphasized since minimal research has been performed on other psychiatric disorders. 2.?BASIC Biochemistry and T863 neurophysiology Tryptophan (TRP) is converted into CFD1 several bioactive molecules, the best known of which is serotonin. However, only a small percentage of TRP is usually metabolized into serotonin. More than 95% of TRP is usually converted into kynurenine (KYN) and its breakdown products, culminating in the generation of nicotinamide adenine dinucleotide (NAD+), an important cellular energy source1 (physique 1). The kynurenines are produced in many different tissues, notably in the liver by the enzyme, tryptophan dioxygenase (((is usually expressed in various immune cells throughout the body, notably dendritic cells, monocytes, and macrophages. Less is known about the more recently discovered enzyme although it is usually more selectively expressed in dendritic cells, liver, kidney, and the brain180 and it does not appear to have a significant effect on peripheral kynurenine concentration181. This review focuses on (hereafter is an alternative nomenclature for isozymes. Alternatively, it may be converted into anthranilic acid by or 3-hydroxykynurenine (3HK) by (expression. is usually activated primarily via the interferon gamma receptor (IFN-R)24, but also through IFN-R-independent pathways, notably the toll-like receptor 4 (TLR4)25 and the synergistic activation of TLR4, the interleukin 1 beta receptor (IL-1R)26, 27, and the tumor necrosis factor alpha receptor (TNFR)27, 28. CNS concentrations of KYN also appear to increase via an but not expression is usually increased in rat brain after systemic LPS administration25, 30, and in human hippocampal progenitor cells, IL-1 was shown to increase transcripts26. 3.1. Relevance to Psychiatry 3.1.1. Mood Disorders There is increasingly persuasive evidence that inflammation plays a pathophysiological role in some cases of depressive disorder, with reports of: (a) depression-associated elevations of circulating pro-inflammatory cytokines31, (b) differential expression of inflammation-related genes in monocytes or peripheral blood mononuclear cells (PBMCs) of subjects with mood disorders32, 33, (c) depressive episodes occurring in 30% of patients receiving immune-stimulating treatments34, (d) the development of depressive symptoms in some healthy participants given low-dose endotoxin35, (e) prospective studies demonstrating a positive association between the concentrations of inflammatory mediators T863 at baseline and the development of cases of major depressive disorder (MDD)36, (f) an epidemiological association between depressive disorder and diseases with an autoimmune or inflammatory component37, 38, (g) higher numbers and/or activation of microglial cells measured with positron emission tomography39, and (h) an increased number and/or activation of microglia/macrophages in depressed suicides at without affecting cytokine levels, indicating that activity within the brain is necessary for the manifestation of depression-like behavior in mice42. Similarly, knockout mice are guarded from the pro-depressive effects of LPS, demonstrating that C at least in mice – neurotoxic kynurenine metabolites are key mediators of inflammation-induced depression-like behaviors43. Clearly, similar kinds of experimental manipulations are not possible to perform in humans. Nevertheless, 30% of patients receiving.