Antibody-mediated neutralization of myelin-associated EphrinB3 accelerates CNS remyelination

• Published in: Acta neuropathologica Vol. 131; no. 2; pp. 281 - 298
• Main Authors: Syed, Yasir A., Zhao, Chao, Mahad, Don, Möbius, Wiebke, Altmann, Friedrich, Foss, Franziska, Sentürk, Aycan, Acker-Palmer, Amparo, Lubec, Gert, Lilley, Kathryn, Franklin, Robin J. M., Nave, Klaus-A., Kotter, Mark R. N.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.02.2016; Springer; Springer Nature B.V
• Subjects: Analysis; Animals; Antibodies; Antigenic determinants; Cells, Cultured; Disease Models, Animal; Ephrin-B3 - genetics; Ephrin-B3 - metabolism; Epitopes - metabolism; Female; Humans; Life sciences; Macrophages - metabolism; Macrophages - pathology; Medicine; Medicine & Public Health; Mice, Knockout; Multiple sclerosis; Multiple Sclerosis - metabolism; Multiple Sclerosis - pathology; Myelin Sheath - metabolism; Myelin Sheath - pathology; Nerve Regeneration - physiology; Neural Stem Cells - metabolism; Neural Stem Cells - pathology; Neurogenesis - physiology; Neurosciences; Oligodendroglia - metabolism; Oligodendroglia - pathology; Original Paper; Pathology; Proteins; Random Allocation; Rats, Sprague-Dawley; Receptor, EphA4 - metabolism; Viral antibodies; United Kingdom > UK; Austria; Germany; EphrinB3; Multiple sclerosis; Remyelination; Oligodendrocytes
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-015-1521-1

Remyelination in multiple sclerosis (MS) lesions often remains incomplete despite the presence of oligodendrocyte progenitor cells (OPCs). Amongst other factors, successful remyelination depends on the phagocytic clearance of myelin debris. However, the proteins in myelin debris that act as potent and selective inhibitors on OPC differentiation and inhibit CNS remyelination remain unknown. Here, we identify the transmembrane signalling protein EphrinB3 as important mediator of this inhibition, using a protein analytical approach in combination with a primary rodent OPC assay. In the presence of EphrinB3, OPCs fail to differentiate. In a rat model of remyelination, infusion of EphrinB3 inhibits remyelination. In contrast, masking EphrinB3 epitopes using antibodies promotes remyelination. Finally, we identify EphrinB3 in MS lesions and demonstrate that MS lesion extracts inhibit OPC differentiation while antibody-mediated masking of EphrinB3 epitopes promotes it. Our findings suggest that EphrinB3 could be a target for therapies aiming at promoting remyelination in demyelinating disease.