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

Britta Engelhardt (1) , Isabella Wimmer (2, 3) , Silvia Tietz (2) , Hideaki Nishihara (2) , Urban Deutsch (4) , Federica Sallusto (5, 6) , Fabien Gosselet (7) , Ruth Lyck (1) , William Muller (8) , Hans P Lassmann (9)

1 Theodor Kocher Institut
2 Theodor Kocher Institute
3 Medizinische Universität Wien = Medical University of Vienna
4 Theodor Kocher Institute
5 Institute for Research in Biomedicine
6 ETH Zürich - Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich]
7 LBHE - Laboratoire de la Barrière Hémato-Encéphalique
8 Northwestern University [Chicago, Ill. USA]
9 University of Vienna [Vienna]

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 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.

Mots clés: vascular permeability; multiple sclerosis; PECAM-1; T-cell diapedesis; blood-brain barrier; endothelial junctions

Domaines: Neurobiologie; Immunité adaptative

Britta Engelhardt, Isabella Wimmer, Silvia Tietz, Hideaki Nishihara, Urban Deutsch, et al.. PECAM-1 Stabilizes Blood-Brain Barrier Integrity and Favors Paracellular T-Cell Diapedesis Across the Blood-Brain Barrier During Neuroinflammation. Frontiers in Immunology, 2019, 10, pp.711. ⟨10.3389/fimmu.2019.00711⟩. ⟨hal-02505535⟩