Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation

Significance Secondary progressive multiple sclerosis (SPMS) inflicts severe and irreversible disability on the affected individuals. Astrocytes are thought to play a central role in the pathogenesis of SPMS. Here, we demonstrate that Sphingosine-1-receptor (S1PR) modulation suppresses pathogenic astrocyte activation and disease progression in an animal model of SPMS. Using functional in vitro assays, we defined direct effects of S1PR modulation on murine and human astrocytes, as well as astrocyte-mediated effects on microglia and proinflammatory monocytes. Finally, in unbiased transcriptome-wide studies on human astrocytes, we identified candidate targets for the modulation of astrocyte function in SPMS. Collectively, this study sheds light on the pathogenesis of SPMS and evaluates the therapeutic value of S1PR modulation in an animal model of SPMS. Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the CNS that causes disability in young adults as a result of the irreversible accumulation of neurological deficits. Although there are potent disease-modifying agents for its initial relapsing-remitting phase, these therapies show limited efficacy in secondary progressive MS (SPMS). Thus, there is an unmet clinical need for the identification of disease mechanisms and potential therapeutic approaches for SPMS. Here, we show that the sphingosine 1-phosphate receptor (S1PR) modulator fingolimod (FTY720) ameliorated chronic progressive experimental autoimmune encephalomyelitis in nonobese diabetic mice, an experimental model that resembles several aspects of SPMS, including neurodegeneration and disease progression driven by the innate immune response in the CNS. Indeed, S1PR modulation by FTY720 in murine and human astrocytes suppressed neurodegeneration-promoting mechanisms mediated by astrocytes, microglia, and CNS-infiltrating proinflammatory monocytes. Genome-wide studies showed that FTY720 suppresses transcriptional programs associated with the promotion of disease progression by astrocytes. The study of the molecular mechanisms controlling these transcriptional modules may open new avenues for the development of therapeutic strategies for progressive MS.

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