2. Academic Validation
  3. Kynurenic acid/GPR35 axis restricts NLRP3 inflammasome activation and exacerbates colitis in mice with social stress

Kynurenic acid/GPR35 axis restricts NLRP3 inflammasome activation and exacerbates colitis in mice with social stress

  • Brain Behav Immun. 2019 Jul;79:244-255. doi: 10.1016/j.bbi.2019.02.009.
Xiao Zheng 1,  Miaomiao Hu 1,  Xiaojie Zang 1,  Qiling Fan 2,  Yali Liu 1,  Yuan Che 1,  Xiaojing Guan 1,  Yuanlong Hou 3,  Guangji Wang 4,  Haiping Hao 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China; Laboratory of Metabolic Regulation and Drug Target Discovery, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
  • 2 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China.
  • 3 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China; Jiangsu Province Key Laboratory of Drug Metabolism, China Pharmaceutical University, Nanjing, Jiangsu, China.
  • 4 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China; Jiangsu Province Key Laboratory of Drug Metabolism, China Pharmaceutical University, Nanjing, Jiangsu, China. Electronic address: guangjiwang@hotmail.com.
  • 5 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China; Laboratory of Metabolic Regulation and Drug Target Discovery, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China; Jiangsu Province Key Laboratory of Drug Metabolism, China Pharmaceutical University, Nanjing, Jiangsu, China. Electronic address: hhp_770505@hotmail.com.
PMID: 30790702 DOI: 10.1016/j.bbi.2019.02.009
Abstract

Psychological stress is well known to increase colitis susceptibility and promote relapse. Metabolic changes are commonly observed under psychological stress, but little is known how this relates to the progression of colitis. Here we show that kynurenic acid (KA) is an endogenous driver of social stress-exacerbated colitis via regulating the magnitude of NLRP3 inflammasome. Chronic social defeat stress (CSDS) in mice induced colonic accumulation of KA, and mice receiving KA during CSDS had defects in colonic NLRP3 inflammasome activation. Mechanistically, KA activated GPR35 signaling to induce autophagy-dependent degradation of NLRP3 in macrophages, thereby suppressing IL-1β production. Socially defeated mice with KA treatment displayed enhanced vulnerability to subsequent dextran sulphate sodium (DSS)-induced colonic injury and inflammatory disturbance, and this effect was reversed by autophagic inhibition that blocked the NLRP3-suppressive effect of KA. Thus, our research describes a mechanism by which KA/GPR35 signaling represses adaptive NLRP3 inflammasome activation to increase colitis susceptibility and suggests a potential metabolic target for the intervention of stress-related colonic disorder.

Keywords

Autophagy; Colitis; GPR35; Immunometabolism; Kynurenic acid; Mucosal immunity; NLRP3 inflammasome; Psychological stress.

Figures
Products