PECAM-1 Stabilizes Blood-Brain Barrier Integrity and Favors Paracellular T-Cell Diapedesis Across the Blood-Brain Barrier During Neuroinflammation

• Published in: Frontiers in immunology Vol. 10; p. 711
• Main Authors: Wimmer, Isabella, Tietz, Silvia, Nishihara, Hideaki, Deutsch, Urban, Sallusto, Federica, Gosselet, Fabien, Lyck, Ruth, Muller, William A., Lassmann, Hans, Engelhardt, Britta
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers 2019; Frontiers Media S.A
• Subjects: Adaptive immunology; Adult; Animals; blood-brain barrier; Blood-Brain Barrier - immunology; Cells, Cultured; endothelial junctions; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Female; Gray Matter - immunology; Humans; Immunology; Life Sciences; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; multiple sclerosis; Multiple Sclerosis - immunology; Neurobiology; Neurogenic Inflammation; Neurons and Cognition; Paracrine Communication; PECAM-1; Platelet Endothelial Cell Adhesion Molecule-1 - genetics; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism; T-cell diapedesis; T-Lymphocyte Subsets - immunology; Th1 Cells - immunology; Transendothelial and Transepithelial Migration; Up-Regulation; vascular permeability; White Matter - immunology; blood-brain barrier; PECAM-1; T-cell diapedesis; endothelial junctions; vascular permeability; multiple sclerosis
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2019.00711

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 gray matter MS lesions. Using a human 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 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 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.