Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis

Authors

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, MercedFollow
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

ORCiD

David M. Ojcius: 0000-0003-1461-4495

Department

Biomedical Sciences

Document Type

Article

Publication Title

Immunity

ISSN

1074-7613

Volume

36

Issue

3

DOI

10.1016/j.immuni.2012.01.009

First Page

401

Last Page

414

Publication Date

3-1-2012

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.

Recommended Citation

Shimada, K., Crother, T. R., Karlin, J., Dagvadori, J., Chiba, N., Chen, S., Ramanujan, V. K., Wolf, A. J., Vergnes, L., Ojcius, D. M., Rentsendorj, A., Vargas, M., Guerrero, C., Wang, Y., Fitzgerald, K. A., Underhill, D. M., Town, T., & Arditi, M. (2012). Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity, 36(3), 401–414. DOI: 10.1016/j.immuni.2012.01.009
https://scholarlycommons.pacific.edu/dugoni-facarticles/11