Blockade of MCAM/CD146 impedes CNS infiltration of T cells over the choroid plexus
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) a...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2018-08-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-018-1276-4 |
| _version_ | 1818541727879790592 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Johanna Breuer |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T22:12:59Z |
| format | Article |
| id | doaj.art-ad681e70065a4e31ad301967c1b2efd7 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-11T22:12:59Z |
| publishDate | 2018-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-ad681e70065a4e31ad301967c1b2efd72022-12-22T00:48:43ZengBMCJournal of Neuroinflammation1742-20942018-08-0115111210.1186/s12974-018-1276-4Blockade of MCAM/CD146 impedes CNS infiltration of T cells over the choroid plexusJohanna Breuer0Eva Korpos1Melanie-Jane Hannocks2Tilman Schneider-Hohendorf3Jian Song4Lisa Zondler5Sebastian Herich6Ken Flanagan7Thomas Korn8Alexander Zarbock9Tanja Kuhlmann10Lydia Sorokin11Heinz Wiendl12Nicholas Schwab13Clinic of Neurology with Institute of Translational Neurology, University of MünsterInstitute of Physiological Chemistry and of Pathobiochemistry, University of MünsterInstitute of Physiological Chemistry and of Pathobiochemistry, University of MünsterClinic of Neurology with Institute of Translational Neurology, University of MünsterInstitute of Physiological Chemistry and of Pathobiochemistry, University of MünsterDepartment of Anesthesiology, University of MünsterClinic of Neurology with Institute of Translational Neurology, University of MünsterProthena Biosciences Inc.Department of Neurology, Technical University of MunichCells-in-Motion Cluster of Excellence, University of MünsterDepartment of Neuropathology, University of MünsterInstitute of Physiological Chemistry and of Pathobiochemistry, University of MünsterClinic of Neurology with Institute of Translational Neurology, University of MünsterClinic of Neurology with Institute of Translational Neurology, University of MünsterAbstract 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.http://link.springer.com/article/10.1186/s12974-018-1276-4MCAMVLA-4CNS-migrationChoroid plexusLaminin 411EAE |
| spellingShingle | 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 Blockade of MCAM/CD146 impedes CNS infiltration of T cells over the choroid plexus Journal of Neuroinflammation MCAM VLA-4 CNS-migration Choroid plexus Laminin 411 EAE |
| title | Blockade of MCAM/CD146 impedes CNS infiltration of T cells over the choroid plexus |
| title_full | Blockade of MCAM/CD146 impedes CNS infiltration of T cells over the choroid plexus |
| title_fullStr | Blockade of MCAM/CD146 impedes CNS infiltration of T cells over the choroid plexus |
| title_full_unstemmed | Blockade of MCAM/CD146 impedes CNS infiltration of T cells over the choroid plexus |
| title_short | Blockade of MCAM/CD146 impedes CNS infiltration of T cells over the choroid plexus |
| title_sort | blockade of mcam cd146 impedes cns infiltration of t cells over the choroid plexus |
| topic | MCAM VLA-4 CNS-migration Choroid plexus Laminin 411 EAE |
| url | http://link.springer.com/article/10.1186/s12974-018-1276-4 |
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