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

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.

The blood–brain barrier in health and disease: Important unanswered questions

“…Leukocyte extravasation across the BBB can be either transcellular or paracellular (Carman et al, 2007; Winger et al, 2014). Levels of ICAM1 and PECAM1 can influence T cell diapedesis route (Abadier et al, 2015; Wimmer et al, 2019), and specific subsets of T cells prefer different routes (Lutz et al, 2017).…”

Study of Usutu virus neuropathogenicity in mice and human cellular models

“…cells were allowed to differentiate on culture inserts in contact with pericytes for 6-7 days to acquire BBB characteristics ( Fig 5A) [46]. These brain-like endothelial cells (hBLECs) express tight junctions and transporters typically observed in brain endothelium [46] and allow to study drugs or cells passage across the BBB [47,48]. hBLECs were infected by USUV on the apical side at the multiplicity of infection (MOI) of 0.1.…”

Differential Expression of CD31 and Von Willebrand Factor on Endothelial Cells in Different Regions of the Human Brain: Potential Implications for Cerebral Malaria Pathogenesis

“…CD31 exhibits mechanosensory properties, which regulates vascular integrity and migration of immune cells [41] in response to changes in osmolarity and varying blood flow [42][43][44][45]. The pattern of expression of CD31 observed in our study implies a variation in the integrity of the BBB in the various regions of the brain.…”