Chronic activation of the inflammasome leads to the development of autoinflammatory diseases; therefore, inflammasome formation needs to be tightly controlled. In Immunity, Guo et al. report that bile acids (BAs) negatively regulate the activation of NLRP3 inflammasomes. BAs signal via the transmembrane receptor TGR5 (encoded by Gpbar) to activate adenylate cyclase, which leads to activation of the kinase PKA. Furthermore, they show that PKA directly phosphorylates mouse NLRP3 at Ser291 (Ser295 of human NLRP3), which enhances the ubiquitination of NLRP3. These BA-induced post-translational modifications of NLRP3 diminish its ability to form 'specks' with the other inflammasome components ASC and pro-caspase-1 and decrease the production of mature IL-1β. Notably, disease-related single-nucleotide polymorphisms have been associated with human GPBAR1. Moreover, agonists of TGR5 suppress the activation of NLRP3 in preclinical mouse models, suggestive of potential therapeutic intervention for some autoinflammatory diseases.

Immunity (27 September 2016) 10.1016/j.immuni.2016.09.008