Research Papers: Immunology:
Chenodeoxycholic acid activates NLRP3 inflammasome and contributes to cholestatic liver fibrosis
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Zizhen Gong1,2,3,*, Jiefei Zhou1,2,3,*, Shengnan Zhao1,2,3,*, Chunyan Tian4,5, Panliang Wang1, Congfeng Xu6, Yingwei Chen2,3, Wei Cai1,2,3 and Jin Wu1,2,3
1 Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
2 Shanghai Institute for Pediatric Research, Shanghai Jiaotong University School of Medicine, Shanghai, China
3 Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
4 State Key Laboratory of Proteomics, National Center for Proteomics Science (Beijing), Beijing Institute of Radiation Medicine, Beijing, China
5 National Engineering Research Center for Protein Drugs, Beijing, China
6 Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai Jiaotong University School of Medicine, Shanghai, China
* These authors have contributed equally to this work
Jin Wu, email:
Wei Cai, email:
Keywords: bile acid, inflammasome, IL-1β, inflammation, liver fibrosis, Immunology and Microbiology Section, Immune response, Immunity
Received: September 09, 2016 Accepted: November 22, 2016 Published: December 04, 2016
Accumulation of hydrophobic bile acids in the liver contributes to cholestatic liver injury. Inflammation induced by excessive bile acids is believed to play a crucial role, however, the mechanisms of bile acids triggered inflammatory response remain unclear. Recent studies have highlighted the effect of NLRP3 inflammasome in mediating liver inflammation and fibrosis. In this study, we for the first time showed that chenodeoxycholic acid (CDCA), the major hydrophobic primary bile acid involved in cholestatic liver injury, could dose-dependently induce NLRP3 inflammasome activation and secretion of pro-inflammatory cytokine-IL-1β in macrophages by promoting ROS production and K+ efflux. Mechanistically, CDCA triggered ROS formation in part through TGR5/EGFR downstream signaling, including protein kinase B, extracellular regulated protein kinases and c-Jun N-terminal kinase pathways. Meanwhile, CDCA also induced ATP release from macrophages which subsequently causes K+ efflux via P2X7 receptor. Furthermore, in vivo inhibition of NLRP3 inflammasome with caspase-1 inhibitor dramatically decreased mature IL-1β level of liver tissue and ameliorated liver fibrosis in bile duct ligation (BDL) mouse model. In conclusion, excessive CDCA may represent an endogenous danger signal to activate NLRP3 inflammasome and initiate liver inflammation during cholestasis. Our finding offers a mechanistic basis to ameliorate cholestatic liver fibrosis by targeting inflammasome activation.
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