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PECAM-1 stabilizes blood-brain barrier integrity and favors paracellular T-Cell diapedesis across the blood-brain barrier during neuroinflammation

  • Wimmer, Isabella Theodor Kocher Institute, University of Bern, Switzerland - Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Austria
  • Tietz, Silvia Theodor Kocher Institute, University of Bern, Switzerland
  • Nishihara, Hideaki Theodor Kocher Institute, University of Bern, Switzerland
  • Deutsch, Urban Theodor Kocher Institute, University of Bern, Switzerland
  • Sallusto, Federica Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Institute of Microbiology, ETH Zürich, Switzerland
  • Gosselet, Fabien Blood-Brain Barrier Laboratory, Université d'Artois, Lens, France
  • Lyck, Ruth Theodor Kocher Institute, University of Bern, Switzerland
  • Muller, William A. Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
  • Lassmann, Hans Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Austria
  • Engelhardt, Britta Theodor Kocher Institute, University of Bern, Switzerland
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    05.04.2019
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  • Frontiers in immunology. - 2019, vol. 10, p. 711
Blood-brain barrier
Endothelial junctions
PECAM-1
T-cell diapedesis
Vascular permeability
Multiple sclerosis
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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  • English
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Pathology, clinical medicine
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https://n2t.net/ark:/12658/srd1319145
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