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TIFA as a crucial mediator for NLRP3 inflammasome

Significance Oxidative and inflammatory stresses (e.g., atheroprone flow and hyperlipidemia) induce innate immune responses in vascular endothelium, of which the assembly and activation of nucleotide oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome constitute a core mechanism. We show that TNF-α receptor-associated factor-interacting protein with a forkhead-associated domain (TIFA) is a mediator of NLRP3 inflammasome in endothelium. The involved regulations include that sterol regulatory element-binding protein 2 transcriptionally induces TIFA (signal 1) and that phosphorylated TIFA causes higher-order assembly of NLRP3 inflammasome (signal 2). Given that sustained innate immune response/activation in endothelium is common to a variety of vascular impairments, TIFA-mediated NLRP3 inflammasome constitutes a pathway by which sustained oxidative and inflammatory stresses lead to dysfunctional endothelium. Toll-like receptor-mediated NF-κB activation is a major innate immune reaction of vascular endothelial cells (ECs) in response to prooxidative and proinflammatory stimuli. We identified that TNF-α receptor-associated factor-interacting protein with a forkhead-associated domain (TIFA) is a regulator of priming (signal 1) and activating (signal 2) signals of nucleotide oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome in ECs. Oxidative and inflammatory stresses such as atheroprone flow and hyperlipidemia induce and activate TIFA in vitro and in vivo. For the priming of signal 1, sterol regulatory element-binding protein 2 transactivates TIFA, which in turn induces NF-κB activation and augments the transcription of NLRP3 inflammasome components. For the activation of signal 2, Akt is involved in TIFA Thr9 phosphorylation, which is essential for TIFA–TIFA homophilic oligomerization. Thr9 phosphorylation-dependent TIFA oligomerization facilitates the higher-order assembly of NLRP3 inflammasome, as indicated by the interaction between TIFA and caspase-1 in the activated ECs. Our results suggest that TIFA is a crucial mediator in the endothelial innate immune response by potentiating and amplifying NLRP3 inflammasome via augmenting signals 1 and 2.