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Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis

Kenichi Shimada1, Timothy R Crother, Justin Karlin

  • 1Division of Pediatrics Infectious Disease and Immunology, Cedars-Sinai Medical Center and David Geffen School of Medicine, UCLA, Los Angeles, CA 90048, USA.

Immunity
|February 21, 2012
PubMed

Insights

Mitochondrial DNA (mtDNA) released during apoptosis activates the NLRP3 inflammasome, driving interleukin-1β (IL-1β) production. This discovery links programmed cell death to inflammasome activation.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • The NLRP3 inflammasome is a key regulator of inflammation, activated by various cellular stress signals.
  • Mitochondrial dysfunction and apoptosis are implicated in inflammasome activation, but the precise mechanisms remain unclear.

Purpose of the Study:

  • To elucidate the role of mitochondrial components in NLRP3 inflammasome activation during apoptosis.
  • To identify the specific molecular link between programmed cell death and inflammasome signaling.

Main Methods:

  • Utilized cell culture models, including macrophages, to study inflammasome activation.
  • Investigated the effects of apoptosis-inducing stimuli and mitochondrial dysfunction on NLRP3 inflammasome activation.
  • Assessed the role of mitochondrial DNA (mtDNA) and its oxidation products in inflammasome activation.
  • Employed biochemical assays to detect interleukin-1β (IL-1β) production and protein-nucleic acid interactions.

Main Results:

  • Mitochondrial apoptotic signaling, triggered by secondary activators like ATP, leads to NLRP3 inflammasome activation and IL-1β production.
  • Release of oxidized mitochondrial DNA (mtDNA) into the cytosol is a critical event that directly binds to and activates the NLRP3 inflammasome.
  • Macrophages lacking mtDNA exhibit significantly reduced IL-1β production despite undergoing apoptosis.
  • The anti-apoptotic protein Bcl-2 modulates mitochondrial dysfunction and NLRP3 inflammasome activation.
  • Oxidized mtDNA binding to NLRP3 and subsequent IL-1β secretion can be inhibited by 8-OH-dG.

Conclusions:

  • Oxidized mitochondrial DNA (mtDNA) released during programmed cell death serves as a direct activator of the NLRP3 inflammasome.
  • This study establishes a crucial link between apoptosis and inflammasome activation, mediated by cytosolic oxidized mtDNA.
  • The findings provide a novel mechanistic understanding of how cellular damage signals trigger inflammatory responses.

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