| First Author | Wu YH | Year | 2014 |
| Journal | Cell Death Differ | Volume | 21 |
| Issue | 3 | Pages | 451-61 |
| PubMed ID | 24270411 | Mgi Jnum | J:229062 |
| Mgi Id | MGI:5750286 | Doi | 10.1038/cdd.2013.165 |
| Citation | Wu YH, et al. (2014) Participation of c-FLIP in NLRP3 and AIM2 inflammasome activation. Cell Death Differ 21(3):451-61 |
| abstractText | Cellular FLICE-inhibitory protein (c-FLIP) is an inhibitor of caspase-8 and is required for macrophage survival. Recent studies have revealed a selective role of caspase-8 in noncanonical IL-1beta production that is independent of caspase-1 or inflammasome. Here we demonstrated that c-FLIP(L) is an unexpected contributor to canonical inflammasome activation for the generation of caspase-1 and active IL-1beta. Hemizygotic deletion of c-FLIP impaired ATP- and monosodium uric acid (MSU)-induced IL-1beta production in macrophages primed through Toll-like receptors (TLRs). Decreased IL-1beta expression was attributed to a reduced activation of caspase-1 in c-FLIP hemizygotic cells. In contrast, the production of TNF-alpha was not affected by downregulation in c-FLIP. c-FLIP(L) interacted with NLRP3 or procaspase-1. c-FLIP is required for the full NLRP3 inflammasome assembly and NLRP3 mitochondrial localization, and c-FLIP is associated with NLRP3 inflammasome. c-FLIP downregulation also reduced AIM2 inflammasome activation. In contrast, c-FLIP inhibited SMAC mimetic-, FasL-, or Dectin-1-induced IL-1beta generation that is caspase-8-mediated. Our results demonstrate a prominent role of c-FLIP(L) in the optimal activation of the NLRP3 and AIM2 inflammasomes, and suggest that c-FLIP could be a valid target for treatment of inflammatory diseases caused by over-activation of inflammasomes. |
