Microglia-derived TNF-? Mediates Endothelial Necroptosis Aggravating Blood Brain–barrier Disruption After Ischemic Stroke

Endothelium(EC)is a key component of blood– brain barrier(BBB),and has an important position in the neurovascular unit.Its dysfunct ion and death after cerebral ischemic/reperfusion(I/R)injury not only promote evolution of neuroinflammation and brain edema,but also increase the risk of intracerebral hemorrhage of thrombolytic therapies.However,the mechanism and specific interventions of EC death after I/R injury are poorly understood.Here weshowed that necroptosis was a mechanism underlying EC death,which promoted BBB breakdown after I/R injury.Treatment of rats with receptor interacting protein kinase 1(RIPK1)-inhibitor,necrostatin-1 reduced endothelial necroptosis and BBB leakage.We furthermore showed that perivascular M1-like microglia-induced endothelial necroptosis leading to BBB disruption requires tumor necrosis factor-?(TNF-?)secreted by M1 type microglia and its receptor,TNF receptor 1(TNFR1),on endothelium as the primary mediators of these effects.More importantly,anti-TNF(infliximab,a potent clinically used drug)treatment significantly ameliorate endothelial necroptosis,BBB destruction and improve strok e outcomes.Our data identify a previously unexplored role for endothelial necroptosis in BBB disruption and suggest infliximab might serve as a potential drug for stroke therapy.