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The von Willebrand factor A1 domain mediates thromboinflammation, aggravating ischemic stroke outcome in mice

Von Willebrand factor (VWF) plays an important role in ischemic stroke. However, the exact mechanism by which VWF mediates progression of ischemic stroke brain damage is not completely understood. Using flow cytometric analysis of single cell suspensions prepared from brain tissue and immunohistoche...

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Autores principales: Denorme, Frederik, Martinod, Kimberly, Vandenbulcke, Aline, Denis, Cécile V., Lenting, Peter J., Deckmyn, Hans, Vanhoorelbeke, Karen, Meyer, Simon F. De
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Fondazione Ferrata Storti 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927893/
https://www.ncbi.nlm.nih.gov/pubmed/32107335
http://dx.doi.org/10.3324/haematol.2019.241042
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author Denorme, Frederik
Martinod, Kimberly
Vandenbulcke, Aline
Denis, Cécile V.
Lenting, Peter J.
Deckmyn, Hans
Vanhoorelbeke, Karen
Meyer, Simon F. De
author_facet Denorme, Frederik
Martinod, Kimberly
Vandenbulcke, Aline
Denis, Cécile V.
Lenting, Peter J.
Deckmyn, Hans
Vanhoorelbeke, Karen
Meyer, Simon F. De
author_sort Denorme, Frederik
collection PubMed
description Von Willebrand factor (VWF) plays an important role in ischemic stroke. However, the exact mechanism by which VWF mediates progression of ischemic stroke brain damage is not completely understood. Using flow cytometric analysis of single cell suspensions prepared from brain tissue and immunohistochemistry, we investigated the potential inflammatory mechanisms by which VWF contributes to ischemic stroke brain damage in a mouse model of cerebral ischemia/reperfusion injury. Twenty-four hours after stroke, flow cytometric analysis of brain tissue revealed that overall white blood cell recruitment in the ipsilesional brain hemisphere of VWF knockout mice was two times lower than that in wildtype mice. More detailed analysis showed a specific reduction of proinflammatory monocytes, neutrophils and T cells in the ischemic brain of VWF knockout mice compared to wild-type mice. Interestingly, histological analysis revealed a substantial number of neutrophils and T cells still within the microcirculation of the stroke brain, potentially contributing to the noreflow phenomenon. Specific therapeutic targeting of the VWF A1 domain in the wild-type mice resulted in reduced numbers of immune cells in the affected brain and protected mice from ischemic stroke brain damage. More specifically, recruitment of proinflammatory monocytes was reduced two-fold, neutrophil recruitment was reduced five-fold and T-cell recruitment was reduced two-fold in mice treated with a VWF A1-targeting nanobody compared to the recruitment in mice receiving a control nanobody. In conclusion, our data identify a potential role for VWF in the recruitment of proinflammatory monocytes, neutrophils and T cells to the ischemic brain through a mechanism that is mediated by its A1 domain.
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spelling pubmed-79278932021-03-05 The von Willebrand factor A1 domain mediates thromboinflammation, aggravating ischemic stroke outcome in mice Denorme, Frederik Martinod, Kimberly Vandenbulcke, Aline Denis, Cécile V. Lenting, Peter J. Deckmyn, Hans Vanhoorelbeke, Karen Meyer, Simon F. De Haematologica Article Von Willebrand factor (VWF) plays an important role in ischemic stroke. However, the exact mechanism by which VWF mediates progression of ischemic stroke brain damage is not completely understood. Using flow cytometric analysis of single cell suspensions prepared from brain tissue and immunohistochemistry, we investigated the potential inflammatory mechanisms by which VWF contributes to ischemic stroke brain damage in a mouse model of cerebral ischemia/reperfusion injury. Twenty-four hours after stroke, flow cytometric analysis of brain tissue revealed that overall white blood cell recruitment in the ipsilesional brain hemisphere of VWF knockout mice was two times lower than that in wildtype mice. More detailed analysis showed a specific reduction of proinflammatory monocytes, neutrophils and T cells in the ischemic brain of VWF knockout mice compared to wild-type mice. Interestingly, histological analysis revealed a substantial number of neutrophils and T cells still within the microcirculation of the stroke brain, potentially contributing to the noreflow phenomenon. Specific therapeutic targeting of the VWF A1 domain in the wild-type mice resulted in reduced numbers of immune cells in the affected brain and protected mice from ischemic stroke brain damage. More specifically, recruitment of proinflammatory monocytes was reduced two-fold, neutrophil recruitment was reduced five-fold and T-cell recruitment was reduced two-fold in mice treated with a VWF A1-targeting nanobody compared to the recruitment in mice receiving a control nanobody. In conclusion, our data identify a potential role for VWF in the recruitment of proinflammatory monocytes, neutrophils and T cells to the ischemic brain through a mechanism that is mediated by its A1 domain. Fondazione Ferrata Storti 2020-02-27 /pmc/articles/PMC7927893/ /pubmed/32107335 http://dx.doi.org/10.3324/haematol.2019.241042 Text en Copyright© 2021 Ferrata Storti Foundation http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
spellingShingle Article
Denorme, Frederik
Martinod, Kimberly
Vandenbulcke, Aline
Denis, Cécile V.
Lenting, Peter J.
Deckmyn, Hans
Vanhoorelbeke, Karen
Meyer, Simon F. De
The von Willebrand factor A1 domain mediates thromboinflammation, aggravating ischemic stroke outcome in mice
title The von Willebrand factor A1 domain mediates thromboinflammation, aggravating ischemic stroke outcome in mice
title_full The von Willebrand factor A1 domain mediates thromboinflammation, aggravating ischemic stroke outcome in mice
title_fullStr The von Willebrand factor A1 domain mediates thromboinflammation, aggravating ischemic stroke outcome in mice
title_full_unstemmed The von Willebrand factor A1 domain mediates thromboinflammation, aggravating ischemic stroke outcome in mice
title_short The von Willebrand factor A1 domain mediates thromboinflammation, aggravating ischemic stroke outcome in mice
title_sort von willebrand factor a1 domain mediates thromboinflammation, aggravating ischemic stroke outcome in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927893/
https://www.ncbi.nlm.nih.gov/pubmed/32107335
http://dx.doi.org/10.3324/haematol.2019.241042
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