Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
National Center for Magnetic Resonance in Wuhan, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, China.
Cell Death Dis. 2019 Jun 20;10(7):487. doi: 10.1038/s41419-019-1716-9.
Endothelium (EC) is a key component of blood-brain barrier (BBB), and has an important position in the neurovascular unit. Its dysfunction 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 we showed 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-α (TNF-α) secreted by M1 type microglia and its receptor, TNF receptor 1 (TNFR1), on endothelium as the primary mediators of these effects. More importantly, anti-TNFα (infliximab, a potent clinically used drug) treatment significantly ameliorate endothelial necroptosis, BBB destruction and improve stroke 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.
内皮细胞（EC）是血脑屏障（BBB）的关键组成部分，在神经血管单元中具有重要地位。脑缺血/再灌注（I/R）损伤后内皮细胞的功能障碍和死亡不仅促进神经炎症和脑水肿的发展，而且增加溶栓治疗后脑出血的风险。然而，内皮细胞在 I/R 损伤后死亡的机制和具体干预措施仍知之甚少。在这里，我们发现坏死性凋亡是内皮细胞死亡的一种机制，它促进了 I/R 损伤后的 BBB 破坏。用受体相互作用蛋白激酶 1（RIPK1）抑制剂 necrostatin-1 治疗大鼠，可减少内皮细胞坏死性凋亡和 BBB 渗漏。我们进一步表明，血管周围 M1 样小胶质细胞诱导的内皮细胞坏死性凋亡导致 BBB 破坏需要 M1 型小胶质细胞分泌的肿瘤坏死因子-α（TNF-α）及其受体 TNF 受体 1（TNFR1）作为这些作用的主要介质。更重要的是，抗 TNF-α（英夫利昔单抗，一种临床上常用的有效药物）治疗可显著改善内皮细胞坏死性凋亡、BBB 破坏，并改善中风预后。我们的数据确定了内皮细胞坏死性凋亡在 BBB 破坏中的一个以前未被探索的作用，并表明英夫利昔单抗可能作为中风治疗的潜在药物。
