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  2. Microglia-derived TNF-α mediates endothelial necroptosis aggravating blood brain-barrier disruption after ischemic stroke

Microglia-derived TNF-α mediates endothelial necroptosis aggravating blood brain-barrier disruption after ischemic stroke

  • Cell Death Dis. 2019 Jun 20;10(7):487. doi: 10.1038/s41419-019-1716-9.
An-Qi Chen 1 Zhi Fang 1 Xiao-Lu Chen 1 Shuai Yang 1 Yi-Fan Zhou 1 Ling Mao 1 Yuan-Peng Xia 1 Hui-Juan Jin 1 Ya-Nan Li 1 Ming-Feng You 1 Xu-Xia Wang 2 Hao Lei 2 Quan-Wei He 3 Bo Hu 4
Affiliations

Affiliations

  • 1 Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 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.
  • 3 Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. hequanwei2016@hust.edu.cn.
  • 4 Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. hubo@mail.hust.edu.cn.
Abstract

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.

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