Participation of c-FLIP in NLRP3 and AIM2 inflammasome activation

• Published in: Cell death and differentiation Vol. 21; no. 3; pp. 451 - 461
• Main 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
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.03.2014
• Subjects: Animals; Apoptosis; Bone marrow; Carrier Proteins - genetics; Carrier Proteins - metabolism; CASP8 and FADD-Like Apoptosis Regulating Protein - metabolism; Cell death; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Down-Regulation; HEK293 Cells; Humans; Immunology; Inflammasomes - metabolism; Interleukin-1beta - metabolism; Laboratory animals; Ligands; Listeria; Macrophages - metabolism; Mice; Molecular biology; NLR Family, Pyrin Domain-Containing 3 Protein; Original Paper; Peptides; Proteins; Signal Transduction; Uric acid; Taiwan
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2013.165

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.