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

Proc Natl Acad Sci U S A. 2022 Jun 28;119(26):e2123247119. doi: 10.1073/pnas.2123247119. Epub 2022 Jun 22.

Abstract

Mitochondria, a highly metabolically active organelle, have been shown to play an essential role in regulating innate immune function. Mitochondrial Ca2+ uptake via the mitochondrial Ca2+ 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 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 NLRP3 (nucleotide-binding domain, leucine-rich repeat containing family, pyrin domain-containing 3) inflammasome by inhibiting phagolysosomal membrane repair. Myeloid deletion of MCU (McuΔmye) 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 McuΔmye macrophages. Mechanistically, we demonstrated that decreased NLRP3 inflammasome activation in McuΔmye macrophages was caused by improved phagolysosomal membrane repair mediated by ESCRT (endosomal sorting complex required for transport)-III complex. Furthermore, McuΔmye 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.

Keywords: ESCRT; MCU; inflammasome; phagosome.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alum Compounds
  • Animals
  • Calcium Channels* / genetics
  • Calcium Channels* / metabolism
  • Caspase 1 / metabolism
  • Disease Models, Animal
  • Endosomal Sorting Complexes Required for Transport
  • Inflammasomes* / metabolism
  • Interleukin-1beta / metabolism
  • Macrophages / metabolism
  • Mice
  • Mitochondrial Proteins* / genetics
  • Mitochondrial Proteins* / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein* / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism
  • Peritonitis* / chemically induced
  • Peritonitis* / metabolism
  • Phagocytosis*

Substances

  • Alum Compounds
  • Calcium Channels
  • Endosomal Sorting Complexes Required for Transport
  • Inflammasomes
  • Interleukin-1beta
  • Mcu protein, mouse
  • Mitochondrial Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • aluminum sulfate
  • Caspase 1