The role and mechanism of TNFRSF21 in promoting necroptosis of vascular endothelial cells and inducing vascular leakage in sepsis

Vascular leakage in sepsis is critical factors in improving the prognosis of septic patients, with limited treatment options targeting underlying molecular mechanisms. Necroptosis is a form of cell death centered around the RIPK1/RIPK3/MLKL pathway, combining both programmed and inflammatory characteristics. However, its role and mechanism in sepsis-induced vascular leakage remain unclear. In vivo and in vitro, CLP and LPS were used to simulate sepsis model. It was found that the expression levels of RIPK1/RIPK3/p-MLKL in septic VECs were significantly increased, and Necroptosis inhibitors significantly improved septic vascular leakage. Transcriptomic and Western blot results suggested that TNFRSF21 plays a key role in Necroptosis. shTNFRSF21 inhibited the formation of necrosome (RIPK3/p-MLKL) in septic VECs, improved vascular leakage in septic rats, and prolonged their survival time. The compound Phen-DC3 of inhibiting TNFRSF21 and the anesthetic remimazolam, both downregulated TNFRSF21, thereby improving septic vascular leakage. Our results suggest that TNFRSF21-regulated Necroptosis plays an important role in septic vascular leakage, and targeting TNFRSF21 inhibition may be a potential therapeutic strategy for septic vascular leakage. KEY MESSAGES: Necroptosis plays a crucial role in sepsis-induced vascular leakage. TNFRSF21 promotes necrosome formation by upregulating RIPK3/p-MLKL, leading to endothelial cell death and disruption of the vascular barrier. The TNFRSF21 inhibitor Phen-DC3 was identified as a compound that improves sepsis-induced vascular leakage, providing a potential new therapeutic strategy for sepsis treatment. The anesthetic remimazolam inhibits TNFRSF21, improving sepsis-induced vascular leakage, offering experimental evidence for the repurposing of existing drugs like remimazolam in the treatment of sepsis.