1. Academic Validation
  2. Kynurenine regulates NLRP2 inflammasome in astrocytes and its implications in depression

Kynurenine regulates NLRP2 inflammasome in astrocytes and its implications in depression

  • Brain Behav Immun. 2020 Aug;88:471-481. doi: 10.1016/j.bbi.2020.04.016.
Qingyu Zhang 1 Yiming Sun 1 Zhang He 1 Ying Xu 1 Xueting Li 1 Jianhua Ding 2 Ming Lu 2 Gang Hu 3
Affiliations

Affiliations

  • 1 Department of Pharmacology, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, Jiangsu 210023, China.
  • 2 Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, China.
  • 3 Department of Pharmacology, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, Jiangsu 210023, China; Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, China. Electronic address: [email protected].
Abstract

Increased kynurenine (Kyn) metabolized from tryptophan (Try) is a biomarker in the immune dysfunction of depression. However, the mechanism by which Kyn change promotes depression is poorly defined. Astrocytes are involved in the neuroinflammation of depression. Among the numerous inflammatory cytokines, interleukin-1β (IL-1β) produced by astrocytic Nod-like receptor protein (NLRP) inflammasome is crucial in the pathogenesis of depression. In the present study, Kyn was shown to be a proinflammatory metabolite in the neuroimmune signaling network mediating depressive-like behavior. First, in chronic mild stress (CMS)-induced depressive mice, the level of Kyn notably increased in the hippocampus, accompanied by the activation of astrocytic NLRP2 inflammasome. Kyn treatment specifically upregulated Nod-like receptor protein 2 (NLPR2) expression in primary mouse astrocytes. Kyn + ATP activated NLRP2 inflammasome, evidenced by increased Caspase-1 expression and IL-1β release. After Kyn treatment, nuclear factor kappa-B (NF-κB) could translocate to the nucleus and bind the promoter of NLRP2, subsequently increased NLRP2 transcription in cultured astrocytes in vitro. Intraperitoneal injection of Kyn activated NLRP2 inflammasome in astrocytes of hippocampus in mice, while NLRP2 knockdown in astrocytes abolished depressive-like behaviors in mice induced by Kyn, suggesting the critical role of NLRP2 in Kyn-induced depression. These findings demonstrate a novel mechanism that Kyn upregulates NLRP2 in an NF-κB-dependent pathway and provide a new strategy for treatment of depression.

Keywords

Astrocyte; Depression; Kynurenine; NLRP2 inflammasome.

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