Cell Biology

Mitochondria, Apoptosis, and the Inflammasome

Sci. Signal.  10 Apr 2012:
Vol. 5, Issue 219, pp. ec106
DOI: 10.1126/scisignal.2003118

Inflammasomes are multimolecular complexes that sense pathogens and endogenous danger signals and stimulate an inflammatory response (see commentary by Martinon). The inflammasome that contains the scaffold protein NLRP3 triggers the production of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18 in response to microbial products and endogenous danger signals such as ATP. Noting that processes such as reactive oxygen species (ROS) production, cytosolic K+ efflux, and mitochondrial dysfunction are implicated in stimulating NLRP3-dependent inflammation, Shimada et al. investigated the mechanism of activation of NLRP3 in mouse macrophages infected with the bacterium Chlamydia pneumoniae. They found that IL-1β production in response to C. pneumoniae was enhanced when macrophages were treated with compounds that disrupted mitochondrial function, such as ATP or nigericin, which triggers K+ efflux. Macrophages treated with proapoptotic stimuli exhibited NLRP3 inflammasome activation and secreted IL-1β. Disruption of mitochondrial function by NLRP3 agonists triggered the release of mitochondrial DNA (mtDNA) into the cytosol, and coimmunoprecipitation assays showed that mtDNA bound directly to NLRP3. Macrophages deficient in mtDNA produced less IL-1β in response to NLRP3 agonists than did wild-type macrophages. Oxidized mtDNA, but not nonoxidized mtDNA, activated the NLRP3 inflammasome in transfected cells, leading to IL-1β production. IL-1β assays and coimmunoprecipitations showed that 8-hydroxy-guanosine, which is generated when DNA undergoes oxidation, competed with oxidized mtDNA for binding to and activation of NLRP3. Together, these data suggest that activators of the NLRP3 inflammasome cause mitochondrial dysfunction, mtDNA oxidation, and release of oxidized mtDNA into the cytosol, where it binds to NLRP3 and stimulates inflammasome assembly, thus resulting in IL-1β production.

K. Shimada, T. R. Crother, J. Karlin, J. Dagvadorj, N. Chiba, S. Chen, V. K. Ramanujan, A. J. Wolf, L. Vergnes, D. M. Ojcius, A. Rentsendorj, M. Vargas, C. Guerrero, Y. Wang, K. A. Fitzgerald, D. M. Underhill, T. Town, M. Arditi, Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36, 401–414 (2012). [PubMed]

F. Martinon, Dangerous liaisons: Mitochondrial DNA meets the NLRP3 inflammasome. Immunity 36, 313–315 (2012). [PubMed]