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

Abstract

Multiple sclerosis (MS) is an in ammatory demyelinating disease of the central nervous system (CNS) mediated by aberrant immune responses. The current immune modulatory therapies are unable to protect and repair the brain damage caused by the immune attack. One of the therapeutic targets for MS is the sphingosine-1-phosphate (S1P) pathways, which signals via sphingosine-1-phosphate receptors 1-5 (S1P 1-5 ), in the CNS and immune cells. In light of the potential neuro-protective properties of S1P signaling, we utilized the S1P 1 -GFP (Green uorescent protein) reporter mice in the cuprizone-induceddemyelination model, to investigate the in vivo S1P-S1P 1 signaling in the CNS. We observed S1P 1 signaling in a subset of neural stem cells in the subventricular zone (SVZ) during demyelination. Additionally, oligodendrocyte progenitor cells in the SVZ and mature oligodendrocytes in the medial corpus callosum (MCC) expressed S1P 1 signaling during remyelination. We did not observe S1P 1 signaling in neurons and astrocytes in the cuprizone model. This approach was unable to determine S1P 1 -GFP signaling in the myeloid cells because of their aberrant GFP expression in GFP reporter mice.Signi cant S1P 1 signaling was observed in lymphocytes during demyelination and in ammation. Our ndings reveal β-arrestin dependent S1P 1 signaling in oligodendrocyte lineage cells, indicating a role of S1P 1 signaling during remyelination.