PECAM-1 stabilizes blood-brain barrier integrity and favors paracellular T-Cell diapedesis across the blood-brain barrier during neuroinflammation
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Wimmer, Isabella
Theodor Kocher Institute, University of Bern, Switzerland - Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Austria
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Tietz, Silvia
Theodor Kocher Institute, University of Bern, Switzerland
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Nishihara, Hideaki
Theodor Kocher Institute, University of Bern, Switzerland
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Deutsch, Urban
Theodor Kocher Institute, University of Bern, Switzerland
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Sallusto, Federica
Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Institute of Microbiology, ETH Zürich, Switzerland
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Gosselet, Fabien
Blood-Brain Barrier Laboratory, Université d'Artois, Lens, France
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Lyck, Ruth
Theodor Kocher Institute, University of Bern, Switzerland
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Muller, William A.
Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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Lassmann, Hans
Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Austria
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Engelhardt, Britta
Theodor Kocher Institute, University of Bern, Switzerland
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Published in:
- Frontiers in immunology. - 2019, vol. 10, p. 711
English
Breakdown of the blood-brain barrier (BBB) and increased immune cell trafficking into the central nervous system (CNS) are hallmarks of the pathogenesis of multiple sclerosis (MS). Platelet endothelial cell adhesion molecule-1 (PECAM-1; CD31) is expressed on cells of the vascular compartment and regulates vascular integrity and immune cell trafficking. Involvement of PECAM-1 in MS pathogenesis has been suggested by the detection of increased levels of soluble PECAM-1 (sPECAM-1) in the serum and CSF of MS patients. Here, we report profound upregulation of cell-bound PECAM-1 in initial (pre-phagocytic) white matter as well as active cortical grey matter MS lesions. Using a human in vitro BBB model we observed that PECAM-1 is not essential for the transmigration of human CD4+ T-cell subsets (Th1, Th1*, Th2, and Th17) across the BBB. Employing an additional in vitro BBB model based on primary mouse brain microvascular endothelial cells (pMBMECs) we show that the lack of endothelial PECAM-1 impairs BBB properties as shown by reduced transendothelial electrical resistance (TEER) and increases permeability for small molecular tracers. Investigating T-cell migration across the BBB under physiological flow by in vitro live cell imaging revealed that absence of PECAM-1 in pMBMECs did not influence arrest, polarization and crawling of effector/memory CD4+ T cells on the pMBMECs. Absence of endothelial PECAM-1 also did not affect the number of T cells able to cross the pMBMEC monolayer under flow, but surprisingly favored transcellular over paracellular T-cell diapedesis. Taken together, our data demonstrate that PECAM-1 is critically involved in regulating BBB permeability and although not required for T-cell diapedesis itself, its presence or absence influences the cellular route of T-cell diapedesis across the BBB. Upregulated expression of cell-bound PECAM-1 in human MS lesions may thus reflect vascular repair mechanisms aiming to restore BBB integrity and paracellular T-cell migration across the BBB as it occurs during CNS immune surveillance.
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Pathology, clinical medicine
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License undefined
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https://n2t.net/ark:/12658/srd1319145
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