Mitochondrial calcium uniporter positively regulates phagocytosis-dependent activation of NLRP3 inflammasome

Abstract

Abstract Mitochondria have been shown to play an essential role in the innate immune function and inflammatory response. Mitochondrial Ca2+ signaling, which is controlled by mitochondrial Ca2+ uniporter (MCU), is a fundamental mechanism regulating mitochondrial metabolism. Accumulative evidence suggests MCU-dependent mitochondrial Ca2+ signaling may bridge the metabolic reprogramming and regulation of immune cell function. However, the mechanism by which MCU regulates inflammation and its related disease remains elusive. Here we report a critical role of MCU in promoting phagocytosis-dependent activation of the NLRP3 inflammasome by dampening phagosome membrane repair. Myeloid deletion of MCU (McuΔmye) resulted in decreased caspase-1 cleavage and IL-1β maturation in response to the challenge with silica and alum, but not ATP and nigericin, in lipopolysaccharide (LPS)-primed macrophages. Stimulation with poly(dA:dT) or flagellin induced a similar IL-1β release between McuΔmye and wild-type (WT) macrophages. Mechanistically, we detected an enhanced phagosomal recruitment of ESCRT (endosomal sorting complex required for transport)-III complex in McuΔmye macrophages after silica or alum stimulation compared to similarly treated WT cells. ESCRT-III complex is known to be essential for repair of phagosomal membrane after damage, suggesting that deletion of MCU might lead to improved phagosomal membrane repair to limit NLRP3 inflammasome activation. Furthermore, McuΔmye mice showed attenuated inflammatory response and tissue damage in a chemically induced colitis model. In sum, our results identify a novel function and mechanism of MCU in regulating phagocytosis-dependent NLRP3 inflammatory response.