Background: 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.
Methods and results: 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.
Conclusion: 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.
There are three isoforms/types of endothelin (identified as ET-1, ET-2, ET3-3) with varying regions of expression and binding to at least four known endothelin receptors, ETA, ETB1, ETB2 and ETC. Recently we saw how endothelin-1 from astrocytes may be affecting the vasculature. In this study a different type of endothelin ET-2 was found to promote remyelination. They started in a model where they can induce myelination in eye nerves that are not normally myelinated, they looked for gene production associated with this effect and came up with some chemokines (factors that direct movement of cells e.g. CXCL13, CCL20, etc) and endothelin-2. This is now yet another factor that can maybe help get myelin back on nerves. If they block endothelin-2 working it stopped remyelination. This is however another instance where the myelinating factor has many other influences besides remyelination. Endothelin-2 can influence blood pressure and ovulation. It is also an attractant of macrophages and it is well known that you need macrophages to clear up the debris before you can get repair, is this the action of ET-2 or could it give you a double whammy.
However because of multiple actions there may be that long term treatments will have side-effects. However we may not need to treat for ever but maybe pulse therapy will be enough to kick start repair using the progenitors (Baby myelinating cells) that are in and around MS lesions. But if we don’t try we won’t know. At least having targets allows us to test this and in the past couple of years there has been a constant stream of targets. Let’s hope some that some of these can make the difference. At least there is now a stream of things to try.