Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis
Department of Medicine, Division of Infectious Diseases and Immunology
Animals; Apoptosis; Carrier Proteins; DNA, Mitochondrial; Gene Expression; Inflammasomes; Interleukin-1beta; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B; Oxidation-Reduction; Proto-Oncogene Proteins c-bcl-2; Salmonella typhimurium; Signal Transduction
We report that in the presence of signal 1 (NF-kappaB), the NLRP3 inflammasome was activated by mitochondrial apoptotic signaling that licensed production of interleukin-1beta (IL-1beta). 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-1beta production, yet still underwent apoptosis. Both binding of oxidized mtDNA to the NLRP3 inflammasome and IL-1beta 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.
Shimada, Kenichi; Crother, Timothy R.; Karlin, Justin; Dagvadorj, Jargalsaikhan; Chiba, Norika; Chen, Shuang; Ramanujan, V. Krishnan; Wolf, Andrea J.; Vergnes, Laurent; Ojcius, David M.; Rentsendorj, Altan; Vargas, Mario; Guerrero, Candace; Wang, Yinsheng; Fitzgerald, Katherine A.; Underhill, David M.; Town, Terrence; and Arditi, Moshe, "Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis" (2012). Infectious Diseases and Immunology Publications and Presentations. 133.