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Antonopoulos, Christina; Russo, Hana M.; El Sanadi, Caroline; Martin, Bradley N.; Li, Xiaoxia; Kaiser, William J.; Mocarski, Edward S.; Dubyak, George R.
Journal of biological chemistry/The Journal of biological chemistry, 08/2015, Volume: 290, Issue: 33Journal Article
We recently described the induction of noncanonical IL-1β processing via caspase-8 recruited to ripoptosome signaling platforms in myeloid leukocytes. Here, we demonstrate that activated NLRP3·ASC inflammasomes recruit caspase-8 to drive IL-1β processing in murine bone marrow-derived dendritic cells (BMDC) independent of caspase-1 and -11. Sustained stimulation (>2 h) of LPS-primed caspase-1-deficient (Casp1/11−/−) BMDC with the canonical NLRP3 inflammasome agonist nigericin results in release of bioactive IL-1β in conjunction with robust caspase-8 activation. This IL-1β processing and caspase-8 activation do not proceed in Nlrp3−/− or Asc−/− BMDC and are suppressed by pharmacological inhibition of caspase-8, indicating that caspase-8 can act as a direct IL-1β-converting enzyme during NLRP3 inflammasome activation. In contrast to the rapid caspase-1-mediated death of wild type (WT) BMDC via NLRP3-dependent pyroptosis, nigericin-stimulated Casp1/11−/− BMDC exhibit markedly delayed cell death via NLRP3-dependent apoptosis. Biochemical analyses of WT and Casp1/11−/− BMDC indicated that caspase-8 is proteolytically processed within detergent-insoluble ASC-enriched protein complexes prior to extracellular export during nigericin treatment. Although nigericin-stimulated caspase-1 activation and activity are only modestly attenuated in caspase-8-deficient (Casp8−/−Rip3−/−) BMDC, these cells do not exhibit the rapid loss of viability of WT cells. These results support a contribution of caspase-8 to both IL-1β production and regulated death signaling via NLRP3 inflammasomes. In the absence of caspase-1, NLRP3 inflammasomes directly utilize caspase-8 as both a pro-apoptotic initiator and major IL-1β-converting protease. In the presence of caspase-1, caspase-8 acts as a positive modulator of the NLRP3-dependent caspase-1 signaling cascades that drive both IL-1β production and pyroptotic death. Background: NLRP3 inflammasomes regulate caspase-1-dependent IL-1β release and pyroptotic death in dendritic cells (DC) and macrophages. Results: Caspase-8 mediates IL-1β production and apoptosis by NLRP3 inflammasomes in caspase-1-deficient DC and facilitates pyroptosis in wild type DC. Conclusion: Caspase-8 is activated within NLRP3 inflammasome signaling platforms. Significance: In addition to caspase-1, NLRP3 inflammasomes engage caspase-8 as an important effector of innate immune signaling responses.
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