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Thrombosis
The von Willebrand factor A1 domain mediates thromboinflammation, aggravating ischemic stroke outcome in mice
Ferrata Storti Foundation
Haematologica 2021 Volume 106(3):819-828
Frederik Denorme,1 Kimberly Martinod,1 Aline Vandenbulcke,1 Cécile V. Denis,2 Peter J. Lenting,2 Hans Deckmyn,1 Karen Vanhoorelbeke1 and Simon F. De Meyer1
1Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium and 2Institut National de la Santé et de la Recherche Médicale, UMR_S 1176, Univ. Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
ABSTRACT
Von Willebrand factor (VWF) plays an important role in ischemic stroke. However, the exact mechanism by which VWF mediates pro- gression of ischemic stroke brain damage is not completely under- stood. 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 wild- type mice. More detailed analysis showed a specific reduction of proinflam- matory 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 no- reflow 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 recruit- ment 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.
Introduction
Ischemic stroke is caused by a blood clot occluding one or multiple cerebral arter- ies, often leading to irreversible brain damage. Unfortunately, treatment options are limited and not always successful. In 2015, stroke deaths accounted for 11.8% of total deaths worldwide, making stroke the second leading cause of death.1 The pathogenesis of ischemic stroke brain damage remains largely unclear and better understanding of the underlying mechanisms is crucial to meet the critical demand for improved stroke therapy.
Remarkably, while successful recanalization of the occluded blood vessel is neces- sary to alleviate ischemic stroke brain injury, it is often not sufficient. Indeed, there is not a strict correlation between vessel recanalization and overall neurological out- come 3 months after a stroke.2 The reasons why efficient recanalization is not always associated with good clinical outcomes are unclear and most likely multifactorial. One key contributor is cerebral ischemia/reperfusion injury. The complex patho- physiology of cerebral ischemia/reperfusion injury includes both thrombotic and inflammatory pathways causing microvascular obstructions, increased blood-brain barrier permeability, and overall neurological deterioration.3
In recent years, the pathophysiological role of von Willebrand factor (VWF) in ischemic stroke has become apparent from both clinical and experimental studies.4,5
Correspondence:
SIMON DE MEYER
Simon.Demeyer@kuleuven.be
Received: October 18, 2019. Accepted: February 25, 2020. Pre-published: February 27, 2020.
https://doi.org/10.3324/haematol.2019.241042
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