The role of TIFA in endothelial innate immunity

Toll-like receptor-mediated NF-κB activation is a major innate immune reaction of vascular endothelial cells (ECs) in response to pro-oxidative and pro-inflammatory stimuli. We identified that TIFA [abbreviated from TNFα receptor-associated factor (TRAF)-interacting protein with a forkhead-associated (FHA) domain] is a novel regulator of both priming (Signal 1) and activating (Signal 2) signals of 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 (SREBP2) transactivates TIFA, which in turn induces NF-κB and augments the transcription of NLRP3 inflammasome components. For the activation of Signal 2, our lab has found that 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 interactions between TIFA and caspase-1 in the activated ECs. Furthermore, we revealed that overexpression of TIFA leads to increased autophagy, monocyte adhesion and pyroptosis, indicationg. 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.