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.

中文翻译：

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Caspase-8支架功能和MLKL调节TLR3下游的NLRP3炎性体激活。

TLR2通过早期的MyD88-IRAK1依赖性途径促进NLRP3炎性体激活，该途径提供了通过第二个钾耗竭信号（信号2）激活炎性体所必需的启动信号（信号1）。在这里，我们显示TLR3与dsRNA的结合通过中间和晚期TRIF / RIPK1 / FADD依赖性途径促进翻译后炎症小体活化。这两个途径都需要支架，但不需要caspase-8或RIPK1的催化功能。只有晚期途径才需要具有激酶功能的RIPK3和MLKL功能。从机制上讲，FADD / caspase-8支架功能在中间途径中提供了翻译后信号1，而在晚期途径中，它有助于RIPK3的寡聚，后者与MLKL一起为炎症小体装配提供了信号1和2。细胞质dsRNA可以独立于TRIF，RIPK1，RIPK3或线粒体DRP1激活NLRP3，但需要野生型巨噬细胞中的FADD / caspase-8才能消除RIPK3抑制作用。我们的研究提供了导致对dsRNA响应导致NLRP3炎性体激活的途径的全面分析。