Participation of c-FLIP in NLRP3 and AIM2 inflammasome activation.

Published

Journal Article

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-1β 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-1β. Hemizygotic deletion of c-FLIP impaired ATP- and monosodium uric acid (MSU)-induced IL-1β production in macrophages primed through Toll-like receptors (TLRs). Decreased IL-1β expression was attributed to a reduced activation of caspase-1 in c-FLIP hemizygotic cells. In contrast, the production of TNF-α 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-1β 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.

Full Text

Duke Authors

Cited Authors

  • Wu, Y-H; Kuo, W-C; Wu, Y-J; Yang, K-T; Chen, S-T; Jiang, S-T; Gordy, C; He, Y-W; Lai, M-Z

Published Date

  • March 2014

Published In

Volume / Issue

  • 21 / 3

Start / End Page

  • 451 - 461

PubMed ID

  • 24270411

Pubmed Central ID

  • 24270411

Electronic International Standard Serial Number (EISSN)

  • 1476-5403

Digital Object Identifier (DOI)

  • 10.1038/cdd.2013.165

Language

  • eng

Conference Location

  • England