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Open Access 01-03-2013 | Original Paper

The neurovascular unit as a selective barrier to polymorphonuclear granulocyte (PMN) infiltration into the brain after ischemic injury

Authors: Gaby Enzmann, Caroline Mysiorek, Roser Gorina, Yu-Jung Cheng, Sharang Ghavampour, Melanie-Jane Hannocks, Vincent Prinz, Ulrich Dirnagl, Matthias Endres, Marco Prinz, Rudi Beschorner, Patrick N. Harter, Michel Mittelbronn, Britta Engelhardt, Lydia Sorokin

Published in: Acta Neuropathologica | Issue 3/2013

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.

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Title: The neurovascular unit as a selective barrier to polymorphonuclear granulocyte (PMN) infiltration into the brain after ischemic injury
Authors: Gaby Enzmann
Caroline Mysiorek
Roser Gorina
Yu-Jung Cheng
Sharang Ghavampour
Melanie-Jane Hannocks
Vincent Prinz
Ulrich Dirnagl
Matthias Endres
Marco Prinz
Rudi Beschorner
Patrick N. Harter
Michel Mittelbronn
Britta Engelhardt
Lydia Sorokin
Publication date: 01-03-2013
Publisher: Springer-Verlag
Published in: Acta Neuropathologica / Issue 3/2013
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-012-1076-3

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

The neurovascular unit as a selective barrier to polymorphonuclear granulocyte (PMN) infiltration into the brain after ischemic injury

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

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