Abstract
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.
Highlights
Multiple sclerosis (MS) is a chronic demyelinating disorder of the central nervous system (CNS), which is characterized by a disease course-dependent degree of inflammation, axonal damage, oligodendrocyte death, and astrocytic scar formation affecting the white and gray matter of brain and spinal cord [1]
In comparison to normal white matter (NWM) from non-neurological controls, platelet endothelial cell adhesion molecule-1 (PECAM-1) expression was more than 5-fold increased in initial white matter multiple sclerosis (MS) lesions (IniL), while it was only slightly upregulated in the periplaque white matter (PPWM) and unchanged in active demyelinating lesions (ActL)
Endothelial PECAM-1 staining was most pronounced in initial MS lesions (Figure 1G), while it was less strong in the PPWM (Figure 1F), active demyelinating lesions (Figure 1H) or the NWM of controls (Figure 1E)
Summary
Multiple sclerosis (MS) is a chronic demyelinating disorder of the central nervous system (CNS), which is characterized by a disease course-dependent degree of inflammation, axonal damage, oligodendrocyte death, and astrocytic scar formation affecting the white and gray matter of brain and spinal cord [1]. In addition to regular adherens junctions established by the VEcadherin/catenin complex, BBB endothelial cells are connected by complex and molecularly unique tight junctions established by members of the claudin and junctional adhesion molecule (JAM) families and the intracellular scaffolding proteins ZO-1, ZO-2, and ZO-3 [reviewed in [7]]. Outside of these organized junctional complexes, the BBB cell-to-cell contacts harbor additional transmembrane proteins such as platelet endothelial cell adhesion molecule-1 (PECAM-1) and CD99, which have been suggested to contribute to the regulation of vascular integrity and immune cell extravasation [reviewed in [7]]
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