Wimmer, Isabella Tietz, Silvia Nishihara, Hideaki Deutsch, Urban Sallusto, Federica Gosselet, Fabien Lyck, Ruth Muller, William A. Lassmann, Hans Engelhardt, Britta 2019-04-05 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. application/pdf https://susi.usi.ch/global/documents/319145 https://localhost:5000/ark:/12658/srd1319145 https://susi.usi.ch/documents/319145/files/Wimmer_FrontImmunol_2019.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.3389/fimmu.2019.00711 info:eu-repo/semantics/altIdentifier/ark/12658/srd1319145 info:eu-repo/semantics/openAccess CC BY Frontiers in immunology. - 2019, vol. 10, p. 711 Blood-brain barrier Endothelial junctions PECAM-1 T-cell diapedesis Vascular permeability Multiple sclerosis info:eu-repo/classification/udc/616 PECAM-1 stabilizes blood-brain barrier integrity and favors paracellular T-Cell diapedesis across the blood-brain barrier during neuroinflammation http://purl.org/coar/resource_type/c_6501