Bile Acids Control Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome.
Reciprocal interactions between the metabolic system and immune cells play pivotal roles in diverse inflammatory diseases, but the underlying mechanisms remain elusive. The activation of bile acid-mediated signaling has been linked to improvement in metabolic syndromes and enhanced control of inflammation. Here, we demonstrated that bile acids inhibited NLRP3 inflammasome activation via the TGR5-cAMP-PKA axis. TGR5 bile acid receptor-induced PKA kinase activation led to the ubiquitination of NLRP3, which was associated with the PKA-induced phosphorylation of NLRP3 on a single residue, Ser 291. Furthermore, this PKA-induced phosphorylation of NLRP3 served as a critical brake on NLRP3 inflammasome activation. In addition, in vivo results indicated that bile acids and TGR5 activation blocked NLRP3 inflammasome-dependent inflammation, including lipopolysaccharide-induced systemic inflammation, alum-induced peritoneal inflammation, and type-2 diabetes-related inflammation. Altogether, our study unveils the PKA-induced phosphorylation and ubiquitination of NLRP3 and suggests TGR5 as a potential target for the treatment of NLRP3 inflammasome-related diseases.
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; Program in Molecular and Cellular Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Chuansheng
C
Guo
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; Department of Toxicology, Zhejiang University School of Public Health, Hangzhou 310058, China.
Shujun
S
Xie
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; Program in Molecular and Cellular Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Zhexu
Z
Chi
Department of Neurology, Zhejiang Provincial People's Hospital, Hangzhou 310014, China.
Jinhua
J
Zhang
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; Program in Molecular and Cellular Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Yangyang
Y
Liu
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; Program in Molecular and Cellular Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Li
L
Zhang
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; Program in Molecular and Cellular Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Mingzhu
M
Zheng
Program in Molecular and Cellular Biology, Zhejiang University School of Medicine, Hangzhou 310058, China; Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Xue
X
Zhang
Department of Toxicology, Zhejiang University School of Public Health, Hangzhou 310058, China.
Dajing
D
Xia
Program in Molecular and Cellular Biology, Zhejiang University School of Medicine, Hangzhou 310058, China; Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Yuehai
Y
Ke
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; Program in Molecular and Cellular Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Linrong
L
Lu
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; Program in Molecular and Cellular Biology, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: diwang@zju.edu.cn.
Di
D
Wang
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D008659:Metabolic Diseases / Q000378:metabolism*; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D001647:Bile Acids and Salts; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D043562:Receptors, G-Protein-Coupled; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases