S1P1 receptor subtype inhibits demyelination and regulates chemokine release in cerebellar slice cultures

Abstract

Sphingosine-1-phosphate receptors (S1PRs) are drug targets for the compound FTY720, which is the first oral therapy developed for treatment of relapsing-remitting multiple sclerosis. S1PRs play a variety of functional roles in the differentiation, proliferation, survival and/or migration of neurons and glia. In this study, rat organotypic cerebellar slice cultures were used to assess whether S1PRs play a role in demyelination induced by lysolecithin (LPC). The data demonstrated that FTY720 and SEW2871 (a S1P1R-specific agonist) inhibited LPC-induced demyelination as assessed by myelin basic protein (MBP) immunofluorescence. Treatment with both drugs for 48 h also induced an increase in S1P1R expression in astrocytes. Moreover, FTY720 and SEW2871 inhibited the release of several chemokines in conditions of LPC-induced demyelination, including LIX (CXCL5), MIP-1alpha, and MIP-3alpha. Taken together, the data suggest that activation of S1P1Rs prevents LPC-induced demyelination via a mechanism involving a reduction of chemotactic chemokine release. The study supports the concept that FTY720 attenuates demyelination by not only preventing S1PR-mediated T cell migration into the CNS but also by limiting cytokine communication between cells of the immune system and the CNS.

Galactosylsphingosine (psychosine)-induced demyelination is attenuated by sphingosine 1-phosphate signalling

“…5A). In agreement with our previous studies (Pritchard et al, 2014;Sheridan and Dev, 2012), pFTY720 attenuated LPC-induced demyelination compared with control, as observed by expression of myelin oligodendrocyte glycoprotein (MOG) (Fig. 5B) and myelin basic protein (MBP) (Fig.…”

“…pFTY720 promotes remyelination as well as limiting the demyelination induced by the bioactive lipid lysolecithin (lysophosphatidylcholine, LPC) (Miron et al, 2010;Sheridan and Dev, 2012). With this in mind, we first determined whether psychosine induced demyelination in cerebellar slices and secondly examined whether pFTY720 attenuated this psychosine-induced demyelination.…”

“…The involvement of pro-inflammatory cytokines in the pathogenesis of demyelination has been previously investigated (di Penta et al, 2013), and a model in which S1PR activation may reduce demyelination via a mechanism involving attenuation of cytokine/ chemokine release has been proposed (Sheridan and Dev, 2012). Hence we investigated whether psychosine treatment would induce the release of the pro-inflammatory cytokines IL6, TNFα and IL1β from organotypic cerebellar slices.…”

“…In addition, modulation of S1PRs also promotes oligodendrocyte differentiation and survival (Dev et al, 2008;Miron et al, 2008b). S1PRs have also been shown to limit events of demyelination and promote remyelination, which are probably mediated by the dampening of pro-inflammatory cytokine levels (Miron et al, 2010;Sheridan and Dev, 2012). Overall, therefore, S1PRs represent an important drug target that can be exploited for use in neuroinflammatory, demyelinating and neurodegenerative diseases, as documented by a growing body of literature (Asle-Rousta et al, 2013;Deogracias et al, 2012).…”

Effect of Fingolimod on Neural Stem Cells: A Novel Mechanism and Broadened Application for Neural Repair

“…28,[46][47][48] Furthermore, it has also been shown that FTY720 can enhance remyelination in organotypic slice cultures. 27,49,50 In vivo studies demonstrated that FTY720 is effective at treating acute EAE by promoting OPC proliferation and differentiation and by stimulating the sonic hedgehog (Shh) signaling pathway. 51 These results, together with our findings, indicate that FTY720 has both anti-inflammatory and neuroregenerative effects.…”