title: The neurovascular unit as a selective barrier to polymorphonuclear granulocyte (PMN) infiltration into the brain after ischemic injury.
abstract: The migration of polymorphonuclear granulocytes (PMN) into the brain parenchyma and release of their abundant proteases are considered the main causes of neuronal cell death and reperfusion injury following ischemia. Yet, therapies targeting PMN egress have been largely ineffective. To address this discrepancy we investigated the temporo-spatial localization of PMNs early after transient ischemia in a murine transient middle cerebral artery occlusion (tMCAO) model and human stroke specimens. Using specific markers that distinguish PMN (Ly6G) from monocytes/macrophages (Ly6C) and that define the cellular and basement membrane boundaries of the neurovascular unit (NVU), histology and confocal microscopy revealed that virtually no PMNs entered the infarcted CNS parenchyma. Regardless of tMCAO duration, PMNs were mainly restricted to luminal surfaces or perivascular spaces of cerebral vessels. Vascular PMN accumulation showed no spatial correlation with increased vessel permeability, enhanced expression of endothelial cell adhesion molecules, platelet aggregation or release of neutrophil extracellular traps. Live cell imaging studies confirmed that oxygen and glucose deprivation followed by reoxygenation fail to induce PMN migration across a brain endothelial monolayer under flow conditions in vitro. The absence of PMN infiltration in infarcted brain tissues was corroborated in 25 human stroke specimens collected at early time points after infarction. Our observations identify the NVU rather than the brain parenchyma as the site of PMN action after CNS ischemia and suggest reappraisal of targets for therapies to reduce reperfusion injury after stroke.
authors.affiliation: Theodor Kocher Institute, University of Bern, Freiestrasse 1, 3012, Bern, Switzerland.
authors.forename: Gaby
authors.initials: G
authors.lastname: Enzmann
authors.forename: Caroline
authors.initials: C
authors.lastname: Mysiorek
authors.forename: Roser
authors.initials: R
authors.lastname: Gorina
authors.forename: Yu-Jung
authors.initials: YJ
authors.lastname: Cheng
authors.forename: Sharang
authors.initials: S
authors.lastname: Ghavampour
authors.forename: Melanie-Jane
authors.initials: MJ
authors.lastname: Hannocks
authors.forename: Vincent
authors.initials: V
authors.lastname: Prinz
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dirnagl
authors.forename: Matthias
authors.initials: M
authors.lastname: Endres
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.forename: Rudi
authors.initials: R
authors.lastname: Beschorner
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Harter
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: Britta
authors.initials: B
authors.lastname: Engelhardt
authors.forename: Lydia
authors.initials: L
authors.lastname: Sorokin
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000950:Antigens, Ly / Q000378:metabolism; D001808:Blood Vessels / Q000473:pathology / Q000503:physiopathology; D001812:Blood-Brain Barrier / Q000473:pathology / Q000503:physiopathology*; D001921:Brain / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004727:Endothelium / Q000473:pathology; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000502:physiology; D005947:Glucose / Q000172:deficiency; D006098:Granulocytes / Q000473:pathology*; D006801:Humans; D000860:Hypoxia; D020244:Infarction, Middle Cerebral Artery / Q000276:immunology* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010100:Oxygen / Q000008:administration & dosage
chemical_list: D015703:Antigens, CD; D000950:Antigens, Ly; D015815:Cell Adhesion Molecules; C494192:Ly-6C antigen, mouse; D005947:Glucose; D010100:Oxygen