title: Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis.
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.
authors.affiliation: Division of Pediatrics Infectious Disease and Immunology, Cedars-Sinai Medical Center and David Geffen School of Medicine, UCLA, Los Angeles, CA 90048, USA.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Shimada
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Crother
authors.forename: Justin
authors.initials: J
authors.lastname: Karlin
authors.forename: Jargalsaikhan
authors.initials: J
authors.lastname: Dagvadorj
authors.forename: Norika
authors.initials: N
authors.lastname: Chiba
authors.forename: Shuang
authors.initials: S
authors.lastname: Chen
authors.forename: V Krishnan
authors.initials: VK
authors.lastname: Ramanujan
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Wolf
authors.forename: Laurent
authors.initials: L
authors.lastname: Vergnes
authors.forename: David M
authors.initials: DM
authors.lastname: Ojcius
authors.forename: Altan
authors.initials: A
authors.lastname: Rentsendorj
authors.forename: Mario
authors.initials: M
authors.lastname: Vargas
authors.forename: Candace
authors.initials: C
authors.lastname: Guerrero
authors.forename: Yinsheng
authors.initials: Y
authors.lastname: Wang
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: David M
authors.initials: DM
authors.lastname: Underhill
authors.forename: Terrence
authors.initials: T
authors.lastname: Town
authors.forename: Moshe
authors.initials: M
authors.lastname: Arditi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D002352:Carrier Proteins / Q000276:immunology* / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000276:immunology* / Q000378:metabolism*; D015870:Gene Expression; D058847:Inflammasomes / Q000276:immunology* / Q000378:metabolism*; D053583:Interleukin-1beta / Q000096:biosynthesis; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010084:Oxidation-Reduction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology; D012486:Salmonella typhimurium / Q000276:immunology / Q000472:pathogenicity; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; D004272:DNA, Mitochondrial; D058847:Inflammasomes; D053583:Interleukin-1beta; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2