Abstract
TLR2 promotes NLRP3 inflammasome activation via an early MyD88-IRAK1-dependent pathway that provides a priming signal (signal 1) necessary for activation of the inflammasome by a second potassium-depleting signal (signal 2). Here we show that TLR3 binding to dsRNA promotes post-translational inflammasome activation through intermediate and late TRIF/RIPK1/FADD-dependent pathways. Both pathways require the scaffolding but not the catalytic function of caspase-8 or RIPK1. Only the late pathway requires kinase competent RIPK3 and MLKL function. Mechanistically, FADD/caspase-8 scaffolding function provides a post-translational signal 1 in the intermediate pathway, whereas in the late pathway it helps the oligomerization of RIPK3, which together with MLKL provides both signal 1 and 2 for inflammasome assembly. Cytoplasmic dsRNA activates NLRP3 independent of TRIF, RIPK1, RIPK3 or mitochondrial DRP1, but requires FADD/caspase-8 in wildtype macrophages to remove RIPK3 inhibition. Our study provides a comprehensive analysis of pathways that lead to NLRP3 inflammasome activation in response to dsRNA.
Highlights
Toll-like receptors (TLRs) are pattern recognition receptors that sense a broad range of microbial ligands leading to NF-kB and IRF3 activation and expression of genes involved in inflammation and other immune responses[1,2]
NLRP3 priming by TLR3 requires TRIF/RIPK1/FADD/caspase-8
Our recent studies showed that stimulation of TLR3 with the synthetic double-stranded RNA (dsRNA) poly(I:C) primes NLRP3 activation through a post-translational, TRIF-dependent pathway designated ‘intermediate pathway’[17]
Summary
Toll-like receptors (TLRs) are pattern recognition receptors that sense a broad range of microbial ligands leading to NF-kB and IRF3 activation and expression of genes involved in inflammation and other immune responses[1,2]. On binding of TLR3 to double-stranded RNA (dsRNA), it recruits TRIF through TIR–TIR homotypic domain interactions resulting in TRIF oligomerization[5] Several outcomes follow this interaction in macrophages, depending on the composition of the complexes that are nucleated by oligomerized TRIF. Our recent studies showed that acute TLR2 stimulation triggers a rapid signalling pathway dependent on MyD88, IRAK1 and IRAK4, that leads to post-translational priming of NLRP3 A second, slightly delayed TLR3- and TRIF-dependent pathway, can lead to post-translational priming of NLRP3 We show that TLR3 stimulation can activate two pathways that promote NLRP3 activation, intermediate and late, depending on the nature of the signalling molecules recruited downstream of the TRIF–RIPK1 complex. Our results provide a comprehensive analysis of the NLRP3 inflammasome pathways activated by dsRNA and provide the first example of signalling by the FADD–caspase-8 complex independent of its catalytic activity
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