| First Author | Dong H | Year | 2022 |
| Journal | Proc Natl Acad Sci U S A | Volume | 119 |
| Issue | 26 | Pages | e2123247119 |
| PubMed ID | 35733245 | Mgi Jnum | J:333473 |
| Mgi Id | MGI:7412754 | Doi | 10.1073/pnas.2123247119 |
| Citation | Dong H, et al. (2022) Mitochondrial calcium uniporter promotes phagocytosis-dependent activation of the NLRP3 inflammasome. Proc Natl Acad Sci U S A 119(26):e2123247119 |
| abstractText | Mitochondria, a highly metabolically active organelle, have been shown to play an essential role in regulating innate immune function. Mitochondrial Ca(2+) uptake via the mitochondrial Ca(2+) uniporter (MCU) is an essential process regulating mitochondrial metabolism by targeting key enzymes involved in the tricarboxylic acid cycle (TCA). Accumulative evidence suggests MCU-dependent mitochondrial Ca(2+) 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 NLRP3 (nucleotide-binding domain, leucine-rich repeat containing family, pyrin domain-containing 3) inflammasome by inhibiting phagolysosomal membrane repair. Myeloid deletion of MCU (Mcu(Deltamye)) resulted in an attenuated phagolysosomal rupture, leading to decreased caspase-1 cleavage and interleukin (IL)-1beta release, in response to silica or alum challenge. In contrast, other inflammasome agonists such as adenosine triphosphate (ATP), nigericin, poly(dA:dT), and flagellin induced normal IL-1beta release in Mcu(Deltamye) macrophages. Mechanistically, we demonstrated that decreased NLRP3 inflammasome activation in Mcu(Deltamye) macrophages was caused by improved phagolysosomal membrane repair mediated by ESCRT (endosomal sorting complex required for transport)-III complex. Furthermore, Mcu(Deltamye) mice showed a pronounced decrease in immune cell recruitment and IL-1beta production in alum-induced peritonitis, a typical IL-1-dependent inflammation model. In sum, our results identify a function of MCU in promoting phagocytosis-dependent NLRP3 inflammatory response via an ESCRT-mediated phagolysosomal membrane repair mechanism. |
