Apoptotic stimuli induce mitochondrial dysfunction, including more generation of ROS and release of mitochondrial DNA. In Immunity, Shimada et al. link apoptosis with more NLRP3-dependent activation of caspase-1 and release of IL-1b. Infection with viable Salmonella or Chlamydia can induce apoptosis-linked activation of NLRP3. Notably, cells must first incur signal 1 to upregulate the synthesis of NLRP3 and pro-IL-1b before receiving an apoptotic signal. Enforced expression of the antiapoptotic protein Bcl-2 attenuates the response by NLRP3. NLRP3 recognizes oxidized mitochondrial DNA released into the cytoplasm after mitochondrial stress. When 8-hydroxy-guanosine is added, it blunts apoptosis-induced secretion of IL-1b by competitively binding to NLRP3. Thus, in sensitized cells, mitochondrial ROS oxidize guanosine residues, and release of this modified mitochondrial DNA triggers NLRP3-dependent inflammasome activation.
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Dempsey, L. Apoptosis and NLRP3 activation. Nat Immunol 13, 358 (2012). https://doi.org/10.1038/ni.2280
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DOI: https://doi.org/10.1038/ni.2280
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