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Immunity. 2016 Oct 18;45(4):802-816. doi: 10.1016/j.immuni.2016.09.008. Epub 2016 Sep 28.

Bile Acids Control Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome.

Author information

1
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.
2
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; Department of Toxicology, Zhejiang University School of Public Health, Hangzhou 310058, China.
3
Department of Neurology, Zhejiang Provincial People's Hospital, Hangzhou 310014, China.
4
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.
5
Department of Toxicology, Zhejiang University School of Public Health, Hangzhou 310058, China.
6
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.

Abstract

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.

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PMID:
27692610
DOI:
10.1016/j.immuni.2016.09.008
[Indexed for MEDLINE]
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