Participation of c-FLIP in NLRP3 and AIM2 inflammasome activation |
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Authors: | Y-H Wu W-C Kuo Y-J Wu K-T Yang S-T Chen S-T Jiang C Gordy Y-W He M-Z Lai |
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Institution: | 1.Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan;2.Institute of Immunology, National Taiwan University, Taipei 10052, Taiwan;3.Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan;4.National Laboratory Animal Center, National Applied Research Laboratories, Tainan 74147, Taiwan;5.Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA |
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Abstract: | 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-FLIPL 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-FLIPL 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-FLIPL 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. |
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Keywords: | c-FLIP inflammasome IL-1β caspase-1 caspase-8 macrophages |
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