The kynurenine pathway: a finger in every pie

Jonathan Savitz, Jonathan Savitz

Abstract

The kynurenine pathway (KP) plays a critical role in generating cellular energy in the form of nicotinamide adenine dinucleotide (NAD+). Because energy requirements are substantially increased during an immune response, the KP is a key regulator of the immune system. Perhaps more importantly in the context of psychiatry, many kynurenines are neuroactive, modulating neuroplasticity and/or exerting neurotoxic effects in part through their effects on NMDA receptor signaling and glutamatergic neurotransmission. As such, it is not surprising that the kynurenines have been implicated in psychiatric illness in the context of inflammation. However, because of their neuromodulatory properties, the kynurenines are not just additional members of a list of inflammatory mediators linked with psychiatric illness, but in preclinical studies have been shown to be necessary components of the behavioral analogs of depression and schizophrenia-like cognitive deficits. Further, as the title suggests, the KP is regulated by, and in turn regulates multiple other physiological systems that are commonly disrupted in psychiatric disorders, including endocrine, metabolic, and hormonal systems. This review provides a broad overview of the mechanistic pathways through which the kynurenines interact with these systems, thus impacting emotion, cognition, pain, metabolic function, and aging, and in so doing potentially increasing 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 utility as treatment response or therapeutic monitoring biomarkers.

Conflict of interest statement

DECLARATION OF INTEREST

No conflicts of interest are declared.

Figures

Figure 1:. Simplified Illustration of the Kynurenine…
Figure 1:. Simplified Illustration of the Kynurenine Pathway.
Tryptophan (TRP) is predominantly converted into kynurenine (KYN) by the indoleamine 2,3-dioxygenase (IDO) isozymes and tryptophan dioxygenase (TDO). IDO-1 is expressed in various immune cells throughout the body, notably dendritic cells, monocytes, and macrophages. Less is known about the more recently discovered IDO-2 enzyme although it is more selectively expressed in dendritic cells, liver, kidney, and the brain and it does not appear to have a significant effect on peripheral kynurenine concentration. This review focuses on IDO-1 (hereafter IDO). TDO-2 is an alternative nomenclature for TDO. KYN can be metabolized into kynurenic acid (KYNA), which is usually considered to be neuroprotective, by the KAT isozymes. Alternatively, it may be converted into anthranilic acid by kynureninase or 3-hydroxykynurenine (3HK) by kynurenine mono-oxygenase (KMO). Metabolism down the latter pathway increases under inflammatory conditions, . 3HK is a free radical generator while quinolinic acid (QA) is a known neurotoxin and gliotoxin. Thus, metabolites in this pathway are usually considered to be neurotoxic. QA is the endogenous source of nicotinamide and nicotinamide adenine dinucleotide (NAD+).
Figure 2:. Heuristic Model of the Pathological…
Figure 2:. Heuristic Model of the Pathological Effects of Neurotoxic Kynurenines.
Under inflammatory conditions circulating macrophages produce more kynurenine (KYN), 3-hydroxykynurenine (3HK), and quinolinic acid (QA). 3HK can cross the blood brain barrier damaging neuronal cells through the production of free radicals. KYN also crosses the blood brain barrier where it is preferentially metabolized into 3HK and QA by microglia. Further, macrophages can infiltrate the brain parenchyma, where they are estimated to produce 32 times more QA than resident microglia. Thus, although QA is usually found in low nanomolar concentrations in the human brain and CSF, a significant increase in QA levels to micromolar concentrations likely occurs in patients with neuroinflammation. QA may contribute to the excitotoxic processes caused by the deficient glutamate reuptake (and paradoxical release) by dysfunctional astrocytes. Dendritic atrophy and remodeling also likely occurs altering functional connectivity. Further, 3HK and QA may damage oligodendrocytes leading to white matter abnormalities. Oligodendrocytes are highly sensitive to inflammation and reductions in their numbers or density are one of the most prominent findings in mood disorders at postmortem. Note that other inflammatory mediators also play an important role in these neuropathological processes. Only the kynurenines are shown in the figure for clarity.
Figure 3:. Simplified Model of the Putative…
Figure 3:. Simplified Model of the Putative Psychosis-Inducing Effects of Kynurenic Acid
Cortical GABAergic interneurons normally exert an inhibitory tone on glutamatergic pyramidal neurons that project to the ventral tegmental area (VTA) and modulate dopaminergic neurotransmission. Excess kynurenic acid production by astrocytes may cause NMDA receptor hypofunction on cortical GABA interneurons leading to reductions in GABAergic neurotransmission and the disinhibition of cortical glutamate projections. Theoretically, this abnormally increased glutamatergic activity causes overactivation of the mesolimbic DA pathway and the excessive release of dopamine in the ventral striatum, ultimately leading to the development of psychosis.
Figure 4:. The Immune-Modulatory Effects of Kynurenine…
Figure 4:. The Immune-Modulatory Effects of Kynurenine Pathway Activation
The kynurenine pathway may explain the counter-intuitive phenomenon of co-occurring inflammation and immunosuppression in depression. Under inflammatory conditions, IDO is upregulated, catalyzing the conversion of tryptophan (TRP) to kynurenine (KYN). KYN is preferentially metabolized down the quinolinic acid (QA) pathway into 3-hydroxykynurenine (3HK), 3-hydroxyanthranilic acid (3HAA), and QA. IDO, KYN and its metabolites exert a variety of immunosuppressive effects, including downregulation of NKC receptors and induction of NKC death; induction of lymphocyte cell-cycle arrest and apoptosis, and downregulation of the T-cell receptor (TCR) (readers left, green arrows). They also promote a tolerogenic environment by facilitating the differentiation of naïve T-cells into regulatory T-cells (Treg) and the development of autoreactive B-cells. This suppression of adaptive immune function has clinical consequences, including increased vulnerability to infectious disease, deficient vaccine-induced immunogenicity, and tumor escape– (reader’s right, blue arrows).

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