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

Enzmann, Gaby; Mysiorek, Caroline; Gorina, Roser; Cheng, Yu-Jung; Ghavampour, Sharang; Hannocks, Melanie-Jane; Prinz, Vincent; Dirnagl, Ulrich; Endres, Matthias; Prinz, Marco; Beschorner, Rudi; Harter, Patrick N.; Mittelbronn, Michel; Engelhardt, Britta; Sorokin, Lydia (2013). The neurovascular unit as a selective barrier to polymorphonuclear granulocyte (PMN) infiltration into the brain after ischemic injury. Acta neuropathologica, 125(3), pp. 395-412. Berlin: Springer-Verlag 10.1007/s00401-012-1076-3

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute

UniBE Contributor:

Enzmann, Gaby and Engelhardt, Britta

ISSN:

0001-6322

Publisher:

Springer-Verlag

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:39

Last Modified:

23 Oct 2019 13:57

Publisher DOI:

10.1007/s00401-012-1076-3

PubMed ID:

23269317

Web of Science ID:

000315334100008

BORIS DOI:

10.7892/boris.16032

URI:

https://boris.unibe.ch/id/eprint/16032 (FactScience: 223582)

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