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

doi:10.1038/s41419-019-1716-9

	Microglia-derived TNF-alpha mediates endothelial necroptosis aggravating blood brain-barrier disruption after ischemic stroke
	Chen, An-Qi 1; Fang, Zhi 1; Chen, Xiao-Lu 1; Yang, Shuai 1; Zhou, Yi-Fan 1; Mao, Ling 1; Xia, Yuan-Peng 1; Jin, Hui-Juan 1; Li, Ya-Nan 1; You, Ming-Feng 1
刊名	CELL DEATH & DISEASE
	2019-06-20
卷号	10 页码:18
ISSN号	2041-4889
DOI	10.1038/s41419-019-1716-9
英文摘要	Endothelium (EC) is a key component of bloodbrain 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, necrostatin1 reduced endothelial necroptosis and BBB leakage. We furthermore showed that perivascular M1-like microgliainduced endothelial necroptosis leading to BBB disruption requires tumor necrosis factor-alpha (TNF-alpha) secreted by M1 type microglia and its receptor, TNF receptor 1 (TNFR1), on endothelium as the primary mediators of these effects. More importantly, anti-TNFa (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.
资助项目	National Key Research & Development Program of China[2018YFC1312200] ; National Natural Science Foundation of China[81571119] ; National Natural Science Foundation of China[81400969] ; National Natural Science Foundation of China[81400970] ; National Natural Science Foundation of China[81771249] ; National Natural Science Foundation of China[81671147] ; National Natural Science Foundation of China[81601027] ; National Key Research and Development Program of China[2016YFC1300600] ; National Research Foundation for the Doctoral Program of Higher Education of China[20120142110068] ; New Century Excellent Talents in University[NCET-10-0406]
WOS关键词	CEREBRAL-ARTERY OCCLUSION ; TUMOR-NECROSIS-FACTOR ; PROGRAMMED NECROSIS ; CELL NECROPTOSIS ; PERMEABILITY ; DEATH ; INFLAMMATION ; ACTIVATION ; RATS ; HEMORRHAGE
WOS研究方向	Cell Biology
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000472435000001
资助机构	National Key Research & Development Program of China ; National Key Research & Development Program of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; National Research Foundation for the Doctoral Program of Higher Education of China ; National Research Foundation for the Doctoral Program of Higher Education of China ; New Century Excellent Talents in University ; New Century Excellent Talents in University ; National Key Research & Development Program of China ; National Key Research & Development Program of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; National Research Foundation for the Doctoral Program of Higher Education of China ; National Research Foundation for the Doctoral Program of Higher Education of China ; New Century Excellent Talents in University ; New Century Excellent Talents in University ; National Key Research & Development Program of China ; National Key Research & Development Program of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; National Research Foundation for the Doctoral Program of Higher Education of China ; National Research Foundation for the Doctoral Program of Higher Education of China ; New Century Excellent Talents in University ; New Century Excellent Talents in University ; National Key Research & Development Program of China ; National Key Research & Development Program of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; National Research Foundation for the Doctoral Program of Higher Education of China ; National Research Foundation for the Doctoral Program of Higher Education of China ; New Century Excellent Talents in University ; New Century Excellent Talents in University
内容类型	期刊论文
源URL	[http://ir.wipm.ac.cn/handle/112942/14484]
专题	中国科学院武汉物理与数学研究所
通讯作者	He, Quan-Wei; Hu, Bo
作者单位	1.Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Neurol, Wuhan, Hubei, Peoples R China 2.Chinese Acad Sci, Wuhan Inst Phys & Math, State Key Lab Magnet Resonance & Atom & Mol Phys, Natl Ctr Magnet Resonance Wuhan, Wuhan, Hubei, Peoples R China
推荐引用方式 GB/T 7714	Chen, An-Qi,Fang, Zhi,Chen, Xiao-Lu,et al. Microglia-derived TNF-alpha mediates endothelial necroptosis aggravating blood brain-barrier disruption after ischemic stroke[J]. CELL DEATH & DISEASE,2019,10:18.
APA	Chen, An-Qi.,Fang, Zhi.,Chen, Xiao-Lu.,Yang, Shuai.,Zhou, Yi-Fan.,...&Hu, Bo.(2019).Microglia-derived TNF-alpha mediates endothelial necroptosis aggravating blood brain-barrier disruption after ischemic stroke.CELL DEATH & DISEASE,10,18.
MLA	Chen, An-Qi,et al."Microglia-derived TNF-alpha mediates endothelial necroptosis aggravating blood brain-barrier disruption after ischemic stroke".CELL DEATH & DISEASE 10(2019):18.