Activation of inflammation by lipopolysaccharide (LPS) is an important innate immune response. Here we investigated the contribution of caspases to the LPS-mediated inflammatory response and discovered distinctive temporal roles of RIPK1 in mediating proinflammatory cytokine production when caspases are inhibited. We propose a biphasic model that differentiates the role of RIPK1 in early versus late phase. The early production of proinflammation cytokines stimulated by LPS with caspase inhibition is mediated by the NF-κB pathway that requires the scaffold function of RIPK1 but is kinase independent. Autocrine production of TNFα in the late phase promotes the formation of a novel TNFR1-associated complex with activated RIPK1, FADD, caspase-8, and key mediators of NF-κB signaling. The production of proinflammatory cytokines in the late phase can be blocked by RIPK1 kinase inhibitor Nec-1s. Our study demonstrates a mechanism by which the activation of RIPK1 promotes its own scaffold function to regulate the NF-κB–mediated proinflammatory cytokine production that is negatively regulated by caspases to restrain inflammatory signaling.
Caspase inhibition prolongs inflammation by promoting a signaling complex with activated RIPK1
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Xinyue Huang, Shuixia Tan, Yanxia Li, Shuangyi Cao, Xingyan Li, Heling Pan, Bing Shan, Lihui Qian, Junying Yuan; Caspase inhibition prolongs inflammation by promoting a signaling complex with activated RIPK1. J Cell Biol 7 June 2021; 220 (6): e202007127. doi: https://doi.org/10.1083/jcb.202007127
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