Bile Acids Control Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome.
Guo, Chuansheng; Xie, Shujun; Chi, Zhexu; Zhang, Jinhua; Liu, Yangyang; Zhang, Li; Zheng, Mingzhu; Zhang, Xue; Xia, Dajing; Ke, Yuehai; Lu, Linrong; Wang, Di
[Article] Immunity. 45(4):802-816, October 18, 2016.

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SUMMARY: 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.

* Bile acids inhibit NLRP3 inflammasome activation

* TGR5-cAMP-PKA axis is involved in BAs-induced NLRP3 inflammasome inhibition

* PKA kinase induces NLRP3 phosphorylation on Ser 291 and the ubiquitination of NLRP3

* TGR5 signaling prevents metabolic disorder via inhibition of NLRP3 inflammasome

(C) 2016Elsevier, Inc.