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Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis
  • Kenichi Shimada, Cedars-Sinai Medical Center
  • Timothy R. Crother, Cedars-Sinai Medical Center
  • Justin Karlin, Cedars-Sinai Medical Center
  • Jargalsaikhan Dagvadori, Cedars-Sinai Medical Center
  • Norika Chiba, Cedars-Sinai Medical Center
  • Shuang Chen, Cedars-Sinai Medical Center
  • V. Krishnan Ramanujan, Cedars-Sinai Medical Center
  • Andrea J. Wolf, Cedars-Sinai Medical Center
  • Laurent Vergnes, University of California, Los Angeles
  • David M. Ojcius, University of California, Merced
  • Altan Rentsendorj, Cedars-Sinai Medical Center
  • Mario Vargas, University of California, Riverside
  • Candace Guerrero, University of California, Riverside
  • Yinsheng Wang, University of California, Riverside
  • Katherine A. Fitzgerald, University of Massachusetts
  • David M. Underhill, Cedars-Sinai Medical Center
  • Terrence Town, Cedars-Sinai Medical Center
  • Moshe Arditi, Cedars-Sinai Medical Center
David M. Ojcius: 0000-0003-1461-4495
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We report that in the presence of signal 1 (NF-κB), the NLRP3 inflammasome was activated by mitochondrial apoptotic signaling that licensed production of interleukin-1β (IL-1β). NLRP3 secondary signal activators such as ATP induced mitochondrial dysfunction and apoptosis, resulting in release of oxidized mitochondrial DNA (mtDNA) into the cytosol, where it bound to and activated the NLRP3 inflammasome. The antiapoptotic protein Bcl-2 inversely regulated mitochondrial dysfunction and NLRP3 inflammasome activation. Mitochondrial DNA directly induced NLRP3 inflammasome activation, because macrophages lacking mtDNA had severely attenuated IL-1β production, yet still underwent apoptosis. Both binding of oxidized mtDNA to the NLRP3 inflammasome and IL-1β secretion could be competitively inhibited by the oxidized nucleoside 8-OH-dG. Thus, our data reveal that oxidized mtDNA released during programmed cell death causes activation of the NLRP3 inflammasome. These results provide a missing link between apoptosis and inflammasome activation, via binding of cytosolic oxidized mtDNA to the NLRP3 inflammasome.
Citation Information
Kenichi Shimada, Timothy R. Crother, Justin Karlin, Jargalsaikhan Dagvadori, et al.. "Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis" Immunity Vol. 36 Iss. 3 (2012) p. 401 - 414 ISSN: 1074-7613
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