Acetate attenuates inflammasome activation through GPR43-mediated Ca 2+ -dependent NLRP3 ubiquitination

Acetatehas been indicated to be elevated and to regulate inflammation in inflammatory and metabolic diseases. The inflammasomeserves as a key component of immune homeostasis, and its dysregulation can lead to various inflammatory disorders. However, little is known about the effects of acetateon inflammasomeactivation and the underlying mechanism. Here, we demonstrate that acetateattenuates inflammasomeactivation via GPR43 in a Ca2+-dependent manner. Through binding to GPR43, acetateactivates the Gq/11 subunit and subsequent phospholipase C-IP3 signaling to decrease Ca2+ mobilization. In addition, acetateactivates soluble adenylyl cyclase(sAC), promotes NLRP3 inflammasomeubiquitination by PKA, and ultimately induces NLRP3 degradation through autophagy. In vivo, acetateprotects mice from NLRP3 inflammasome-dependent peritonitis and LPS-induced endotoxemia. Collectively, our research demonstrates that acetateregulates the NLRP3 inflammasomevia GPR43 and Ca2+-dependent mechanisms, which reveals the mechanism of metabolite-mediated NLRP3 inflammasomeattenuation and highlights acetateas a possible therapeutic strategy for NLRP3 inflammasome-related diseases.