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, 45 (4), 802-816

Bile Acids Control Inflammation and Metabolic Disorder Through Inhibition of NLRP3 Inflammasome

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Bile Acids Control Inflammation and Metabolic Disorder Through Inhibition of NLRP3 Inflammasome

Chuansheng Guo et al. Immunity.

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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.

Comment in

  • PKA Has the Gall to Oppose NLRP3
    CJ Groß et al. Immunity 45 (4), 707-709. PMID 27760332. - Review
    The involvement of the NLRP3 inflammasome in inflammatory diseases has generated interest in identifying endogenous mechanisms that inhibit NLRP3. In this issue of Immuni …

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