title: Identification of endothelin 2 as an inflammatory factor that promotes central nervous system remyelination.
abstract: The development of new regenerative therapies for multiple sclerosis is hindered by the lack of potential targets for enhancing remyelination. The study of naturally regenerative processes such as the innate immune response represents a powerful approach for target discovery to solve this problem. By 'mining' these processes using transcriptional profiling we can identify candidate factors that can then be tested individually in clinically-relevant models of demyelination and remyelination. Here, therefore, we have examined a previously described in vivo model of the innate immune response in which zymosan-induced macrophage activation in the retina promotes myelin sheath formation by oligodendrocytes generated from transplanted precursor cells. While this model is not itself clinically relevant, it does provide a logical starting point for this study as factors that promote myelination must be present. Microarray analysis of zymosan-treated retinae identified several cytokines (CXCL13, endothelin 2, CCL20 and CXCL2) to be significantly upregulated. When tested in a cerebellar slice culture model, CXCL13 and endothelin 2 promoted myelination and endothelin 2 also promoted remyelination. In studies to identify the receptor responsible for this regenerative effect of endothelin 2, analysis of both remyelination following experimental demyelination and of different stages of multiple sclerosis lesions in human post-mortem tissue revealed high levels of endothelin receptor type B in oligodendrocyte lineage cells. Confirming a role for this receptor in remyelination, small molecule agonists and antagonists of endothelin receptor type B administered in slice cultures promoted and inhibited remyelination, respectively. Antagonists of endothelin receptor type B also inhibited remyelination of experimentally-generated demyelination in vivo. Our work therefore identifies endothelin 2 and the endothelin receptor type B as a regenerative pathway and suggests that endothelin receptor type B agonists represent a promising therapeutic approach to promote myelin regeneration.
authors.affiliation: MRC Centre for Regenerative Medicine and multiple sclerosis Society/University of Edinburgh Centre for Translational Research, Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Tracy J
authors.initials: TJ
authors.lastname: Yuen
authors.forename: Kory R
authors.initials: KR
authors.lastname: Johnson
authors.forename: Veronique E
authors.initials: VE
authors.lastname: Miron
authors.forename: Chao
authors.initials: C
authors.lastname: Zhao
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Quandt
authors.forename: Marie C
authors.initials: MC
authors.lastname: Harrisingh
authors.forename: Matthew
authors.initials: M
authors.lastname: Swire
authors.forename: Anna
authors.initials: A
authors.lastname: Williams
authors.forename: Henry F
authors.initials: HF
authors.lastname: McFarland
authors.forename: Robin J M
authors.initials: RJ
authors.lastname: Franklin
authors.forename: Charles
authors.initials: C
authors.lastname: Ffrench-Constant
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D003711:Demyelinating Diseases / Q000378:metabolism / Q000503:physiopathology*; D019333:Endothelin-2 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006041:Goats; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D046228:Microarray Analysis / Q000295:instrumentation / Q000379:methods; D009416:Nerve Regeneration / Q000502:physiology*; D011817:Rabbits; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B / Q000819:agonists / Q000502:physiology*
chemical_list: D019333:Endothelin-2; D018836:Inflammation Mediators; D044023:Receptor, Endothelin B