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

Yasir A Syed, Chao Zhao, Don Mahad, Wiebke Möbius, Friedrich Altmann, Franziska Foss, Aycan Sentürk, Amparo Acker-Palmer, Gert Lubec, Kathryn Lilley, Robin J M Franklin, Klaus-A Nave, Mark R N Kotter

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)281-98
Number of pages18
JournalActa Neuropathologica
Volume131
Issue number2
Early online date19 Dec 2015
DOIs
Publication statusPublished - Feb 2016

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