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Acta Neuropathologica
Published in: Acta Neuropathologica 2/2015

01-02-2015 | Original Paper

Very-late-antigen-4 (VLA-4)-mediated brain invasion by neutrophils leads to interactions with microglia, increased ischemic injury and impaired behavior in experimental stroke

Authors: Jens Neumann, Monika Riek-Burchardt, Josephine Herz, Thorsten R. Doeppner, Rebecca König, Heiko Hütten, Eloho Etemire, Linda Männ, Anika Klingberg, Thomas Fischer, Michael W. Görtler, Hans-Jochen Heinze, Peter Reichardt, Burkhart Schraven, Dirk M. Hermann, Klaus G. Reymann, Matthias Gunzer

Published in: Acta Neuropathologica | Issue 2/2015

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Abstract

Neuronal injury from ischemic stroke is aggravated by invading peripheral immune cells. Early infiltrates of neutrophil granulocytes and T-cells influence the outcome of stroke. So far, however, neither the timing nor the cellular dynamics of neutrophil entry, its consequences for the invaded brain area, or the relative importance of T-cells has been extensively studied in an intravital setting. Here, we have used intravital two-photon microscopy to document neutrophils and brain-resident microglia in mice after induction of experimental stroke. We demonstrated that neutrophils immediately rolled, firmly adhered, and transmigrated at sites of endothelial activation in stroke-affected brain areas. The ensuing neutrophil invasion was associated with local blood–brain barrier breakdown and infarct formation. Brain-resident microglia recognized both endothelial damage and neutrophil invasion. In a cooperative manner, they formed cytoplasmic processes to physically shield activated endothelia and trap infiltrating neutrophils. Interestingly, the systemic blockade of very-late-antigen-4 immediately and very effectively inhibited the endothelial interaction and brain entry of neutrophils. This treatment thereby strongly reduced the ischemic tissue injury and effectively protected the mice from stroke-associated behavioral impairment. Behavioral preservation was also equally well achieved with the antibody-mediated depletion of myeloid cells or specifically neutrophils. In contrast, T-cell depletion more effectively reduced the infarct volume without improving the behavioral performance. Thus, neutrophil invasion of the ischemic brain is rapid, massive, and a key mediator of functional impairment, while peripheral T-cells promote brain damage. Acutely depleting T-cells and inhibiting brain infiltration of neutrophils might, therefore, be a powerful early stroke treatment.
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Metadata
Title
Very-late-antigen-4 (VLA-4)-mediated brain invasion by neutrophils leads to interactions with microglia, increased ischemic injury and impaired behavior in experimental stroke
Authors
Jens Neumann
Monika Riek-Burchardt
Josephine Herz
Thorsten R. Doeppner
Rebecca König
Heiko Hütten
Eloho Etemire
Linda Männ
Anika Klingberg
Thomas Fischer
Michael W. Görtler
Hans-Jochen Heinze
Peter Reichardt
Burkhart Schraven
Dirk M. Hermann
Klaus G. Reymann
Matthias Gunzer
Publication date
01-02-2015
Publisher
Springer Berlin Heidelberg
Published in
Acta Neuropathologica / Issue 2/2015
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-014-1355-2

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