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

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

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

146 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)395-412
Number of pages18
JournalActa Neuropathologica
Volume125
Issue number3
DOIs
Publication statusPublished - Mar 2013
Externally publishedYes

Keywords

  • Human
  • Migration
  • Mouse
  • Neurovascular unit
  • Polymorphonuclear granulocyte

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