title: Farnesoid X Receptor Regulation of the NLRP3 Inflammasome Underlies Cholestasis-Associated Sepsis.
abstract: Cholestasis is a common complication of sepsis, and the increased plasma levels of bile acids are predictive of sepsis-associated mortality. However, the exact mechanism by which cholestasis aggravates sepsis development remains elusive. Here, we show that bile acids are danger-associated molecular patterns (DAMPs) that can activate both signal 1 and 2 of the NLRP3 inflammasome in inflammatory macrophages. Mechanistically, bile acids induce a prolonged calcium influx and activate the NLRP3 inflammasome synergistically with ATP. Experimental cholestasis sensitizes, while cholestyramine, a bile acid sequestrant, protects mice from LPS-induced sepsis. FXR negatively regulates the NLRP3 inflammasome via physical interaction with NLRP3 and caspase 1. Fxr-null mice are more sensitive, while FXR-overexpressing mice are more resistant, to endoxemia shock. These findings suggest that bile acids and FXR play pivotal roles in sepsis via controlling the NLRP3 inflammasome, and that targeting FXR may represent a therapeutic strategy for cholestasis-associated sepsis.
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Haiping
authors.initials: H
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100871, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100871, China.
authors.forename: Changtao
authors.initials: C
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Che
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100871, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100871, China.
authors.forename: Songyang
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Shogo
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism, China Pharmaceutical University, Nanjing 210009, China. Electronic address: 1019731203@cpu.edu.cn.
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: gonzalef@mail.nih.gov.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D002779:Cholestasis / Q000150:complications* / Q000378:metabolism*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D007555:Isoxazoles / Q000494:pharmacology; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D000067996:RAW 264.7 Cells; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D018805:Sepsis / Q000209:etiology* / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002118:Calcium; D020170:Caspase 1; D058847:Inflammasomes; D007555:Isoxazoles; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C492716:Nlrp3 protein, mouse; C412815:GW 4064
keywords: NLRP3 inflammasome; bile acids; cholestasis; damage-associated molecular patterns; farnesoid X receptor; protein-protein interaction; sepsis