| First Author | Antonopoulos C | Year | 2015 |
| Journal | J Biol Chem | Volume | 290 |
| Issue | 33 | Pages | 20167-84 |
| PubMed ID | 26100631 | Mgi Jnum | J:224602 |
| Mgi Id | MGI:5688413 | Doi | 10.1074/jbc.M115.652321 |
| Citation | Antonopoulos C, et al. (2015) Caspase-8 as an Effector and Regulator of NLRP3 Inflammasome Signaling. J Biol Chem 290(33):20167-84 |
| abstractText | We recently described the induction of noncanonical IL-1beta 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-1beta 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-1beta in conjunction with robust caspase-8 activation. This IL-1beta 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-1beta-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-1beta 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-1beta-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-1beta production and pyroptotic death. |
