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

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 ametabolic 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.