Identification of endothelin 2 as an inflammatory factor that promotes central nervous system remyelination
Open accessAbstract
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.
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M2 depletion decreased the number of nodes of Ranvier, shown by reduced paranodal Caspr localization flanking nodal Ankyrin-G.
“Second, we demonstrated a decrease in the number of nodes of Ranvier normally indicative of compact myelin27, 28 by showing reduced paranodal Caspr localization (flanking nodal Ankyrin-G) (Fig. 5g, h).”
From M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination (2013) · cites this paper as [28]
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- Authors
- Yuen, T. J., Johnson, K. R., Miron, V. E., Zhao, C., Quandt, J., Harrisingh, M. C., Swire, M., Williams, A., McFarland, H. F., Franklin, R. J. M., & ffrench-Constant, C.
- Affiliations
- National Institutes of Health (US)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Multiple Sclerosis Society (GB)
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-03-21
- Volume
- 136
- Issue
- 4
- Pages
- 1035-1047
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC3613712
- OpenAlex
- W2089851064
- Cited by
- 80
- References
- 52
- Citations by year
- 2025: 3 · 2024: 5 · 2023: 7 · 2022: 3 · 2021: 5 · 2020: 4 · 2019: 12 · 2018: 5 · 2017: 8 · 2016: 9 · 2015: 6 · 2014: 8 · 2013: 5
- FWCI
- 7.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Brain (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UEA Digital Repository (University of East Anglia) (acceptedVersion)
- Funders
- Wellcome Trust (079249)
- Parkinson's UK (G0909)
- Multiple Sclerosis Society
- Rosetrees Trust
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- endothelin-2, endothelin B receptor, remyelination, multiple sclerosis, myelination, oligodendrocytes, innate immune response, CXCL13, CCL20, CXCL2, demyelination, cerebellar slice cultures
- MeSH terms
- Animals, Central Nervous System, Cerebellum, Demyelinating Diseases, Female, Goats, Humans, Nerve Regeneration, Rabbits, Rats, Inbred F344, Rats, Sprague-Dawley, Inflammation Mediators, Endothelin-2, Receptor, Endothelin B, Microarray Analysis, Mice, Rats
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