title: Chenodeoxycholic acid activates NLRP3 inflammasome and contributes to cholestatic liver fibrosis.
abstract: 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.
authors.affiliation: Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Shanghai Institute for Pediatric Research, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
authors.forename: Zizhen
authors.initials: Z
authors.lastname: Gong
authors.affiliation: Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Shanghai Institute for Pediatric Research, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
authors.forename: Jiefei
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Shanghai Institute for Pediatric Research, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
authors.forename: Shengnan
authors.initials: S
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Proteomics, National Center for Proteomics Science (Beijing), Beijing Institute of Radiation Medicine, Beijing, China.|National Engineering Research Center for Protein Drugs, Beijing, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Tian
authors.affiliation: Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Panliang
authors.initials: P
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Congfeng
authors.initials: C
authors.lastname: Xu
authors.affiliation: Shanghai Institute for Pediatric Research, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Shanghai Institute for Pediatric Research, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cai
authors.affiliation: Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Shanghai Institute for Pediatric Research, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Wu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D002635:Chenodeoxycholic Acid / Q000633:toxicity*; D002779:Cholestasis / Q000150:complications* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000378:metabolism; D058847:Inflammasomes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta; D007728:Kupffer Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008026:Ligation; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
chemical_list: D061945:Caspase Inhibitors; C513561:Gpbar1 protein, mouse; C587672:IL1B protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D043562:Receptors, G-Protein-Coupled; D002635:Chenodeoxycholic Acid; D000255:Adenosine Triphosphate; C541485:EGFR protein, mouse; D066246:ErbB Receptors; C505409:Casp3 protein, mouse; D053148:Caspase 3; D011188:Potassium
keywords: IL-1β; Immune response; Immunity; Immunology and Microbiology Section; bile acid; inflammasome; inflammation; liver fibrosis