Blockade of MCAM/CD146 impedes CNS infiltration of T cells over the choroid plexus

Journal of Neuroinflammation

Alexander Zarbock¹  Nicholas Schwab²  Johanna Breuer²  Heinz Wiendl²  Sebastian Herich²  Tilman Schneider-Hohendorf²  Lisa Zondler³  Thomas Korn⁴  Tanja Kuhlmann⁵  Eva Korpos⁶  Lydia Sorokin⁶  Melanie-Jane Hannocks⁶  Jian Song⁶  Ken Flanagan⁷ 

[1] Cells-in-Motion Cluster of Excellence, University of Münster;Clinic of Neurology with Institute of Translational Neurology, University of Münster;Department of Anesthesiology, University of Münster;Department of Neurology, Technical University of Munich;Department of Neuropathology, University of Münster;Institute of Physiological Chemistry and of Pathobiochemistry, University of Münster;Prothena Biosciences Inc.;

关键词: MCAM;    VLA-4;    CNS-migration;    Choroid plexus;    Laminin 411;    EAE;   

DOI  :  10.1186/s12974-018-1276-4

来源: DOAJ

【 摘 要 】

Abstract Background Very late antigen 4 (VLA-4; integrin α4β1) is critical for transmigration of T helper (TH) 1 cells into the central nervous system (CNS) under inflammatory conditions such as multiple sclerosis (MS). We have previously shown that VLA-4 and melanoma cell adhesion molecule (MCAM) are important for trans-endothelial migration of human TH17 cells in vitro and here investigate their contribution to pathogenic CNS inflammation. Methods Antibody blockade of VLA-4 and MCAM is assessed in murine models of CNS inflammation in conjunction with conditional ablation of α4-integrin expression in T cells. Effects of VLA-4 and MCAM blockade on lymphocyte migration are further investigated in the human system via in vitro T cell transmigration assays. Results Compared to the broad effects of VLA-4 blockade on encephalitogenic T cell migration over endothelial barriers, MCAM blockade impeded encephalitogenic T cell migration in murine models of MS that especially depend on CNS migration across the choroid plexus (CP). In transgenic mice lacking T cell α4-integrin expression (CD4::Itga4 −/− ), MCAM blockade delayed disease onset. Migration of MCAM-expressing T cells through the CP into the CNS was restricted, where laminin 411 (composed of α4, β1, γ1 chains), the proposed major ligand of MCAM, is detected in the endothelial basement membranes of murine CP tissue. This finding was translated to the human system; blockade of MCAM with a therapeutic antibody reduced in vitro transmigration of MCAM-expressing T cells across a human fibroblast-derived extracellular matrix layer and a brain-derived endothelial monolayer, both expressing laminin α4. Laminin α4 was further detected in situ in CP endothelial-basement membranes in MS patients’ brain tissue. Conclusions Our findings suggest that MCAM-laminin 411 interactions facilitate trans-endothelial migration of MCAM-expressing T cells into the CNS, which seems to be highly relevant to migration via the CP and to potential future clinical applications in neuroinflammatory disorders.

【 授权许可】

Unknown