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.
journal_name
Immunityjournal_title
Immunityauthors
Guo C,Xie S,Chi Z,Zhang J,Liu Y,Zhang L,Zheng M,Zhang X,Xia D,Ke Y,Lu L,Wang Ddoi
10.1016/j.immuni.2016.09.008subject
Has Abstractpub_date
2016-10-18 00:00:00pages
802-816issue
4eissn
1074-7613issn
1097-4180pii
S1074-7613(16)30352-1journal_volume
45pub_type
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