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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2018

Open Access 01-12-2018 | Research

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

Authors: Johanna Breuer, Eva Korpos, Melanie-Jane Hannocks, Tilman Schneider-Hohendorf, Jian Song, Lisa Zondler, Sebastian Herich, Ken Flanagan, Thomas Korn, Alexander Zarbock, Tanja Kuhlmann, Lydia Sorokin, Heinz Wiendl, Nicholas Schwab

Published in: Journal of Neuroinflammation | Issue 1/2018

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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.
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Metadata
Title
Blockade of MCAM/CD146 impedes CNS infiltration of T cells over the choroid plexus
Authors
Johanna Breuer
Eva Korpos
Melanie-Jane Hannocks
Tilman Schneider-Hohendorf
Jian Song
Lisa Zondler
Sebastian Herich
Ken Flanagan
Thomas Korn
Alexander Zarbock
Tanja Kuhlmann
Lydia Sorokin
Heinz Wiendl
Nicholas Schwab
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2018
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-018-1276-4

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