2014 journal article

Participation of c-FLIP in NLRP3 and AIM2 inflammasome activation

Cell Death & Differentiation, 21(3), 451–461.

By: Y. Wu*, W. Kuo *, Y. Wu *, K. Yang *, S. Chen*, S. Jiang *, C. Gordy* , Y. He *, M. Lai *

author keywords: c-FLIP; inflammasome; IL-1 beta; caspase-1; caspase-8; macrophages
MeSH headings : Animals; CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism; Carrier Proteins / genetics; Carrier Proteins / metabolism; DNA-Binding Proteins / genetics; DNA-Binding Proteins / metabolism; Down-Regulation; HEK293 Cells; Humans; Inflammasomes / metabolism; Interleukin-1beta / metabolism; Macrophages / metabolism; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Peptides; Signal Transduction
TL;DR: It is demonstrated that c-FLIPL is an unexpected contributor to canonical inflammasome activation for the generation of caspase-1 and active IL-1β and suggest that c -FLIP could be a valid target for treatment of inflammatory diseases caused by over-activation of inflamMASomes. (via Semantic Scholar)
Source: ORCID
Added: August 24, 2021

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.