Bile Acids Control Inflammatory Diseases Through Inhibition Of NLRP3 Inflammasome

Reciprocal interactions between the metabolic system and immune cells play pivotal roles in the pathogenesis of diverse inflammatory diseases,but the underlying mechanisms are still unclear.The activation of bile acid-mediated signaling has been linked to improvement in metabolic syndromes and enhanced control of inflammation.Activation of the NLRP3 inflammasome triggers the caspase-1-dependent maturation and release of several pro-inflammatory cytokines,including interleukin-β(IL-1β)and IL-18.Excessive activation of the inflammasome is therefore involved in the pathogenesis of several inflammatory disorders,including type-2 diabetes(T2D),atherosclerosis,gout,and Alzheimer’s disease,suggesting that this activation needs to be tightly controlled.Although recent studies have extensively investigated the NLRP3 inflammasome,little is known about its regulatory networks,especially the endogenous mechanisms.Also,a better understanding of these regulatory mechanisms is required for the development of effective therapeutic treatment for NLRP3-related inflammatory diseases.Here we demonstrate that bile acids specifically inhibit NLRP3 inflammasome activation and related caspase-1 activation,IL-1β secretion and ASC speck formation.Study on mechanism finds that Bile acids can activate PKA via TGR5 receptor,and then PKA directly phosphorylates NLRP3 Ser291,leading to NLRP3 ubiquitination.Subsequent functional experiments indicate that NLRP3 Ser291 phosphorylation and ubiquitination induced by PKA plays vital roles in inhibition of NLRP3 inflammasome activation.Further in vivo assays suggest that bile acids can suppress pathogenesis of inflammatory diseases,including sepsis,peritonitis and T2D.In light of our study,targeting TGR5 may lead to new insights and treatments for NLRP3 inflammasome-related diseases.