Visualizing Sphingosine-1-Phosphate Receptor 1(S1P₁) Signaling During Central Nervous System De- and Remyelination

Multiple sclerosis (MS) is an inflammatory-demyelinating disease of the central nervous system (CNS) mediated by aberrant auto-reactive immune responses. The current immune-modulatory therapies are unable to protect and repair immune-mediated neural tissue damage. One of the therapeutic targets in MS is the sphingosine-1-phosphate (S1P) pathway which signals via sphingosine-1-phosphate receptors 1-5 (S1P_1-5). S1P receptors are expressed predominantly on immune and CNS cells. Considering the potential neuroprotective properties of S1P signaling, we utilized S1P₁-GFP (Green fluorescent protein) reporter mice in the cuprizone-induced demyelination model to investigate in vivo S1P - S1P₁ signaling in the CNS. We observed S1P₁ signaling in a subset of neural stem cells in the subventricular zone (SVZ) during demyelination. During remyelination, S1P₁ signaling is expressed in oligodendrocyte progenitor cells in the SVZ and mature oligodendrocytes in the medial corpus callosum (MCC). In the cuprizone model, we did not observe S1P₁ signaling in neurons and astrocytes. We also observed β-arrestin-dependent S1P₁ signaling in lymphocytes during demyelination and CNS inflammation. Our findings reveal β-arrestin-dependent S1P₁ signaling in oligodendrocyte lineage cells implying a role of S1P₁ signaling in remyelination.