Title

Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis

UMMS Affiliation

Department of Medicine, Division of Infectious Diseases and Immunology

Publication Date

3-23-2012

Document Type

Article

Subjects

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

Disciplines

Immunology and Infectious Disease

Abstract

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.

Journal/Book/Conference Title

Immunity

Comments

Citation: Immunity. 2012 Mar 23;36(3):401-14. Epub 2012 Feb 16. Link to article on publisher's site

Related Resources

Link to Article in PubMed

PubMed ID

22342844