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.

Molecular Signals Involved in Human B Cell Migration into the Retina:In VitroInvestigation of ICAM-1, VCAM-1, and CXCL13

“…(28) While identification of CXCL13 in non-diseased human neural retina and retinal pigment epithelium is a new finding, the recent publication by Yuen et al . (29) corroborates our observation in studies of myelination in the Fischer 344 rat retina. Chan et al .…”

Oligodendrocyte-Encoded HIF Function Couples Postnatal Myelination and White Matter Angiogenesis

“…We crossed conditional HIF1α(fl/fl) and HIF2α(fl/fl) mutants to compound homozygosity (hereafter called HIF1/2α(fl/fl)) with PLP-creERT2 (Doerflinger et al, 2003). Given dramatic hypomyelination observed in the cerebellar white matter of Sox10-cre, VHL(fl/fl) mice (Figure S1C), we utilized a cerebellar explant culture assay suitable to quantify changes in postnatal myelination and compact myelin paranode formation (Fancy et al, 2011b; Yuen et al, 2013). We generated cerebellar explants from P0-P1 transgenic mice and added tamoxifen (which did not affect survival) to induce acute Cre-mediated excision of HIF1/2 α in OLs (Figure 2A, Figure S2A).…”

Oligodendrocyte regeneration: Its significance in myelin replacement and neuroprotection in multiple sclerosis

“…Although ET-1 directly inhibits OPC differentiation and migration in vitro (Gadea et al, 2009), it is the indirect regulation of Jagged1 expression on reactive astrocytes that is proposed to inhibit OPC differentiation following demyelination (Hammond et al, 2014). ET-2 is also implicated in the regulation of CNS remyelination, as it has been shown to promote OPC differentiation and remyelination in a model of innate immunity (Yuen et al, 2013). However, a link between ET-2 and Notch signaling has not been identified to our knowledge.…”