Abstract
The family of sphingosine-1-phosphate receptors (S1PRs) is G-protein-coupled, comprised of subtypes S1PR1-S1PR5 and activated by the endogenous ligand S1P. The phosphorylated version of Fingolimod (pFTY720), an oral therapy for multiple sclerosis (MS), induces S1PR1 internalisation in T cells, subsequent insensitivity to S1P gradients and sequestering of these cells within lymphoid organs, thus limiting immune response. S1PRs are also expressed in neuronal and glial cells where pFTY720 is suggested to directly protect against lysolecithin-induced deficits in myelination state in organotypic cerebellar slices. Of note, the effect of pFTY720 on immune cells already migrated into the CNS, prior to treatment, has not been well established. We have previously found that organotypic slice cultures do contain immune cells, which, in principle, could also be regulated by pFTY720 to maintain levels of myelin. Here, a mouse organotypic cerebellar slice and splenocyte co-culture model was thus used to investigate the effects of pFTY720 on splenocyte-induced demyelination. Spleen cells isolated from myelin oligodendrocyte glycoprotein immunised mice (MOG-splenocytes) or from 2D2 transgenic mice (2D2-splenocytes) both induced demyelination when co-cultured with mouse organotypic cerebellar slices, to a similar extent as lysolecithin. As expected, in vivo treatment of MOG-immunised mice with FTY720 inhibited demyelination induced by MOG-splenocytes. Importantly, in vitro treatment of MOG- and 2D2-splenocytes with pFTY720 also attenuated demyelination caused by these cells. In addition, while in vitro treatment of 2D2-splenocytes with pFTY720 did not alter cell phenotype, pFTY720 inhibited the release of the pro-inflammatory cytokines such as interferon gamma (IFNγ) and interleukin 6 (IL6) from these cells. This work suggests that treatment of splenocytes by pFTY720 attenuates demyelination and reduces pro-inflammatory cytokine release, which likely contributes to enhanced myelination state induced by pFTY720 in organotypic cerebellar slices.
Highlights
The family of sphingosine 1-phosphate receptors (S1PRs) are Gprotein coupled and designated as receptor subtypes 1-5 (S1PR15) [1,2,3,4,5]
The overlap of myelin basic protein (MBP) and neurofilament H (NFH) likely indicates that the oligodendrocytes may be wrapping axons, but is not proof-positive for the presence of compact myelin [31,32]
While we describe the co-localization of MBP and NFH staining as the level of myelination, it should be noted that this measure does not indicate the presence of compact myelin
Summary
The family of sphingosine 1-phosphate receptors (S1PRs) are Gprotein coupled and designated as receptor subtypes 1-5 (S1PR15) [1,2,3,4,5]. These receptor, in particular the S1PR1 subtype, have been described over the last decade as important modulators of immune cell migration [6]. Some studies show that a subpopulation of regulatory T cells (Tregs) may be functionally augmented by pFTY720 [14,15,16,17], which has been suggested as potentially beneficial in autoimmune or inflammatory illnesses. Further studies examining the effects of pFTY720 on these T cell subpopulations may prove useful
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