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Immunity. 2012 Mar 23;36(3):401-14. doi: 10.1016/j.immuni.2012.01.009. Epub 2012 Feb 16.

Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis.

Author information

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

Abstract

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.

PMID:
22342844
PMCID:
PMC3312986
DOI:
10.1016/j.immuni.2012.01.009
[Indexed for MEDLINE]
Free PMC Article

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