Microglia-derived TNF-α mediates endothelial necroptosis aggravating blood brain-barrier disruption after ischemic stroke.
An-qi Chen,Zhi Fang,Xiao-Lu Chen,Shuai Yang,Yifan Zhou,Ling Mao,Yuan-Peng Xia,Huijuan Jin,Yanan Li,Mingfeng You,X. Wang,Hao Lei,Quan-Wei He,Bo Hu +13 more
TLDR
Anti-TNFα (infliximab, a potent clinically used drug) treatment significantly ameliorate endothelial necroptosis, BBB destruction and improve stroke outcomes and suggest infliximab might serve as a potential drug for stroke therapy.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.read more
Citations
More filters
Journal ArticleDOI
Regulation of blood-brain barrier integrity by microglia in health and disease: A therapeutic opportunity.
TL;DR: Characteristics of M1 proinflammatory and M2 anti-inflammatory microglia are highlighted and how these distinct phenotypes modulate BBB physiology are described to help develop novel treatment approaches for neurological diseases.
Journal ArticleDOI
Modulators of microglia activation and polarization in ischemic stroke (Review).
TL;DR: This review aimed to provide a comprehensive overview of microglia activation, their functions and changes, and the modulators of these processes, including transcription factors, membrane receptors, ion channel proteins and genes, in ischemic stroke.
Journal ArticleDOI
The semantics of microglia activation: neuroinflammation, homeostasis, and stress.
TL;DR: In this paper, a review of the role of microglia in pathological and physiological contexts is presented, and a framework is proposed to better describe changes in micro-glia1 phenotype and function in chronic stress.
Journal ArticleDOI
Quantitative proteomics of acutely-isolated mouse microglia identifies novel immune Alzheimer's disease-related proteins.
Srikant Rangaraju,Eric B. Dammer,Syed Ali Raza,Tianwen Gao,Hailian Xiao,Ranjita Betarbet,Duc M. Duong,James A. Webster,Chadwick M. Hales,James J. Lah,Allan I. Levey,Nicholas T. Seyfried +11 more
TL;DR: A comprehensive proteomic study of adult mouse microglia derived from acute neuro inflammation and AD models is reported, highlighting shared and unique microglial proteomic changes in acute neuroinflammation aging and AD mouse models and identifying novel roles for microglian proteins in human neurodegeneration.
Journal ArticleDOI
Immune Cells in the BBB Disruption After Acute Ischemic Stroke: Targets for Immune Therapy?
TL;DR: In this paper, the authors highlight the role of circulating and cerebral immune cells in BBB disruption and the crosstalk between them following acute ischemic stroke and discuss potential and effective immunotherapeutic targets to regulate BBB permeability.
References
More filters
Journal ArticleDOI
Guidelines for the Early Management of Patients With Acute Ischemic Stroke A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association
William J. Powers,Alejandro A. Rabinstein,Teri Ackerson,Opeolu Adeoye,Nicholas C. Bambakidis,Kyra J. Becker,José Biller,Michael D. Brown,Bart M. Demaerschalk,Brian L. Hoh,Edward C. Jauch,Chelsea S. Kidwell,Thabele M Leslie-Mazwi,Bruce Ovbiagele,Phillip A. Scott,Kevin N. Sheth,Andrew M. Southerland,Deborah V. Summers,David L. Tirschwell +18 more
TL;DR: These guidelines supersede the prior 2007 guidelines and 2009 updates and support the overarching concept of stroke systems of care and detail aspects of stroke care from patient recognition; emergency medical services activation, transport, and triage; through the initial hours in the emergency department and stroke unit.
Journal ArticleDOI
Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association.
Emelia J. Benjamin,Salim S. Virani,Clifton W. Callaway,Alanna M. Chamberlain,Alex R. Chang,Susan Cheng,Stephanie E. Chiuve,Mary Cushman,Francesca N. Delling,Rajat Deo,Sarah D. de Ferranti,Jane F. Ferguson,Myriam Fornage,Cathleen Gillespie,Carmen R. Isasi,Monik C. Jiménez,Lori C. Jordan,Suzanne E. Judd,Daniel T. Lackland,Judith H. Lichtman,Lynda D. Lisabeth,Simin Liu,Chris T. Longenecker,Pamela L. Lutsey,Jason Mackey,David B. Matchar,Kunihiro Matsushita,Michael E. Mussolino,Khurram Nasir,Martin O'Flaherty,Latha Palaniappan,Ambarish Pandey,Dilip K. Pandey,Mathew J. Reeves,Matthew D. Ritchey,Carlos J. Rodriguez,Gregory A. Roth,Wayne D. Rosamond,Uchechukwu K.A. Sampson,Gary Satou,Svati H. Shah,Nicole L. Spartano,David L. Tirschwell,Connie W. Tsao,Jenifer H. Voeks,Joshua Z. Willey,John T. Wilkins,Jason H Y Wu,Heather M. Alger,Sally S. Wong,Paul Muntner +50 more
TL;DR: The Statistical Update represents the most up-to-date statistics related to heart disease, stroke, and the cardiovascular risk factors listed in the AHA's My Life Check - Life’s Simple 7, which include core health behaviors and health factors that contribute to cardiovascular health.
Journal ArticleDOI
Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association.
William J. Powers,Alejandro A. Rabinstein,Teri Ackerson,Opeolu Adeoye,Nicholas C. Bambakidis,Kyra J. Becker,José Biller,Michael D. Brown,Bart M. Demaerschalk,Brian L. Hoh,Edward C. Jauch,Chelsea S. Kidwell,Thabele M Leslie-Mazwi,Bruce Ovbiagele,Phillip A. Scott,Kevin N. Sheth,Andrew M. Southerland,Deborah V. Summers,David L. Tirschwell +18 more
TL;DR: These guidelines detail prehospital care, urgent and emergency evaluation and treatment with intravenous and intra-arterial therapies, and in-hospital management, including secondary prevention measures that are appropriately instituted within the first 2 weeks.
Journal ArticleDOI
Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury
Alexei Degterev,Zhihong Huang,Michael Boyce,Yaqiao Li,Prakash Jagtap,Noboru Mizushima,Gregory D. Cuny,Timothy J. Mitchison,Michael A. Moskowitz,Junying Yuan +9 more
TL;DR: It is demonstrated that necroptosis contributes to delayed mouse ischemic brain injury in vivo through a mechanism distinct from that of apoptosis and offers a new therapeutic target for stroke with an extended window for neuroprotection.
Journal ArticleDOI
Molecular mechanisms of necroptosis: an ordered cellular explosion.
TL;DR: Evidence now reveals that necrosis can also occur in a regulated manner, and necroptosis participates in the pathogenesis of diseases, including ischaemic injury, neurodegeneration and viral infection, thereby representing an attractive target for the avoidance of unwarranted cell death.
Related Papers (5)
Inflammatory mechanisms in ischemic stroke: role of inflammatory cells.
Rong Jin,Guojun Yang,Guohong Li +2 more