Regulation of proinflammatory monocyte activation by the kynurenine–AhR axis underlies immunometabolic control of depressive behavior in mice

Abstract

Elevated kynurenine (Kyn) production from tryptophan (Trp) metabolism is a biomarker of immune dysregulation in depression, but its mechanistic contributions to the behavioral symptoms are poorly defined. In this study, Kyn was shown to be a metabolic regulator of proinflammatory monocytes that orchestrated peripheral immune activation and neuroinflammation in depressive mice. Kyn-induced depressive behavior was paralleled by brain infiltration of proinflammatory monocytes and astrocytic activation. Kyn enhanced chemokine (C-C motif) ligand-2-mediated chemotaxis of monocytes and their proinflammatory capability on cocultured astrocytes in vitro, which involved the activation of aryl hydrocarbon receptor (AhR) signaling. Kyn augmented, whereas pharmacological AhR blockade rescued, systemic inflammation-induced monocyte trafficking, neuroimmune disturbance, and depressive-like behavior in mice. The behavior-exacerbating effects of the Kyn-AhR axis were dampened with prior depletion of functional monocytes in the periphery. The findings in our study extend understanding of an immunologic effect of Kyn that links Trp metabolism and inflammatory signaling in depression pathology, with potential therapeutic implications for depressive disorders.-Zang, X., Zheng, X., Hou, Y., Hu, M., Wang, H., Bao, X., Zhou, F., Wang, G., Hao, H. Regulation of proinflammatory monocyte activation by the kynurenine-AhR axis underlies immunometabolic control of depressive behavior in mice.

Twin study shows association between monocyte chemoattractant protein-1 and kynurenic acid in cerebrospinal fluid

“…Particularly, interferon gamma (IFN-γ), but also neopterin, a marker for IFN-γ activity [ 18 ], have been associated with an upregulation of several neuroactive kynurenine metabolites such as KYNA and QUIN in CSF [ 19 , 20 ]. In accordance with our findings, studies on rodents showed that manipulation of TRP degradation affects MCP-1 levels [ 7 , 5 , 6 , 8 ] and MCP-1 seems to play a role in neurotransmission such as dopamine release [ 21 ]. Clinical CSF studies on kynurenine metabolites and inflammatory markers are rare.…”

“…Monocyte chemoattractant protein 1 (MCP-1), also known as chemokine ligand 2 (CCL2), is involved in the recruitment of macrophages to infection sites within the central nervous system (CNS) [4], and preclinical studies have demonstrated a relationship between MCP-1 and the kynurenine pathway. In mice, for example, reduction of indoleamine 2,3-dioxygenase (IDO)-the mediating enzyme of tryptophan degradation-resulted in lower MCP-1 levels [5,6], and plasma kynurenine correlated with MCP-1 gene expression within the CNS [7]. In a study on in vitro cells of human monocytes, prior exposure to kynurenine had an enhancing effect on MCP-1-induced transmigration [8].…”

The Aryl Hydrocarbon Receptor and the Nervous System

“…This is coherent with genome-wide association studies (GWAS) that show an association between AhR expression (and the regulation of KYN-biosynthesizing enzymes, together with the levels of KYN) and the severity of major depressive disorders [ 181 ], or by a recent study on the damages induced by the KYN/AhR following experimental stroke [ 182 ]. One suspected mechanism would be similar to the demyelinating processes observed in AhR-knockout mouse, a stimulated recruitment of pro-inflammatory monocytes and activation of astrocytes by chemokine ligand 2 (CCL2) whose expression would be enhanced by KYN [ 183 ].…”

Nutritional Therapy to Modulate Tryptophan Metabolism and Aryl Hydrocarbon-Receptor Signaling Activation in Human Diseases

“…Moreover, germ-free mice exhibit a deficiency in AhR agonists and show increased susceptibility to chronic stress and anxiety and depression-like behavior [ 107 ]. Furthermore, in a study using LPS-induced depression model, Kyn was associated with increased systemic inflammation-induced monocyte trafficking, mediating neuroimmune dysregulation and enhanced depression-like behavior [ 108 ]. Contrary, pharmacological inhibition of AhR and circulatory monocyte clearance decreased levels of LPS and Kyn and reduced the depressive symptoms in mice [ 108 ], indicating that Kyn and AhR are critical for immunoregulation and depression.…”