Mitochondrial calcium uniporter promotes phagocytosis-dependent activation of the NLRP3 inflammasome

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 119; no. 26; p. e2123247119
• Main Authors: Dong, Hong, Zhao, Bao, Chen, Jianwen, Liu, Zihao, Li, Xinghui, Li, Lupeng, Wen, Haitao
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 28.06.2022
• Subjects: Adenosine triphosphate; Alum Compounds; Animals; ATP; Biological Sciences; Calcium (mitochondrial); Calcium Channels - genetics; Calcium Channels - metabolism; Calcium influx; Calcium ions; Calcium signalling; Caspase 1 - metabolism; Caspase-1; Cell activation; Disease Models, Animal; Domains; Endosomal Sorting Complexes Required for Transport; Flagellin; IL-1β; Immune response; Immune system; Inflammasomes; Inflammasomes - metabolism; Inflammation; Inflammatory response; Interleukin 1; Interleukin-1beta - metabolism; Leucine; Macrophages; Macrophages - metabolism; Membranes; Metabolism; Mice; Mitochondria; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Nigericin; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Nucleotides; Peritonitis; Peritonitis - chemically induced; Peritonitis - metabolism; Phagocytosis; Pyrin protein; Repair; Silica; Tricarboxylic acid cycle; phagosome; ESCRT; inflammasome; MCU
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2123247119

Mitochondria, a highly metabolically active organelle, have been shown to play an essential role in regulating innate immune function. Mitochondrial Ca uptake via the mitochondrial Ca 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 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 ( ) resulted in an attenuated phagolysosomal rupture, leading to decreased caspase-1 cleavage and interleukin (IL)-1β 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-1β release in macrophages. Mechanistically, we demonstrated that decreased NLRP3 inflammasome activation in macrophages was caused by improved phagolysosomal membrane repair mediated by ESCRT (endosomal sorting complex required for transport)-III complex. Furthermore, mice showed a pronounced decrease in immune cell recruitment and IL-1β 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.