Abstract
Acetate has been indicated to be elevated and to regulate inflammation in inflammatory and metabolic diseases. The inflammasome serves as a key component of immune homeostasis, and its dysregulation can lead to various inflammatory disorders. However, little is known about the effects of acetate on inflammasome activation and the underlying mechanism. Here, we demonstrate that acetate attenuates inflammasome activation via GPR43 in a Ca2+-dependent manner. Through binding to GPR43, acetate activates the Gq/11 subunit and subsequent phospholipase C-IP3 signaling to decrease Ca2+ mobilization. In addition, acetate activates soluble adenylyl cyclase (sAC), promotes NLRP3 inflammasome ubiquitination by PKA, and ultimately induces NLRP3 degradation through autophagy. In vivo, acetate protects mice from NLRP3 inflammasome-dependent peritonitis and LPS-induced endotoxemia. Collectively, our research demonstrates that acetate regulates the NLRP3 inflammasome via GPR43 and Ca2+-dependent mechanisms, which reveals the mechanism of metabolite-mediated NLRP3 inflammasome attenuation and highlights acetate as a possible therapeutic strategy for NLRP3 inflammasome-related diseases.
Highlights
The inflammasome is a series of multiprotein complexes that serve as a platform to promote interleukin (IL)-1β secretion and pyroptosis[1]
We found that acetate suppressed the ATP- or nigericin-induced production of IL-1β and IL-18 in a dose-dependent manner (Fig. 1a–d)
We found that acetate suppressed IL-1β and IL-18 production in response to pretreatment, simultaneous treatment or post treatment with LPS and nigericin (Fig. 2a, b)
Summary
The inflammasome is a series of multiprotein complexes that serve as a platform to promote interleukin (IL)-1β secretion and pyroptosis[1]. The NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome comprises the NOD-like receptor, the adaptor protein ASC and caspase-1 and is considered to play a crucial role in the immune response to pathogens[2]. The regulation of NLRP3 inflammasome activation has emerged as a therapeutic target for inflammasome-related illnesses. Several metabolites, such as short-chain fatty acids, dopamine and bile acid, have been reported to be involved in NLRP3 inflammasome regulation[5,6,7]. By binding to transmembrane G-proteincoupled receptor-5 (TGR5) or dopamine receptor D1
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