Abstract
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 (S1P1-5). 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.
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adapted from Kono et al. (2014). b S1P1 knock-in mice are crossed with H2B-GFP mice to generate S1P1-GFP-signaling mice. c Experimental design of the cuprizone-induced demyelination model. Arrb2; β-arrestin-2, TEV; Tobacco etch virus, tTA; tetracycline-controlled transactivator, IRES; internal ribosome entry site, GFP; Green fluorescence protein, S1pr1; S1P receptor 1 gene, S1P1; S1P receptor 1
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Abbreviations
- CC:
-
Corpus Callosum
- CNS:
-
Central Nervous System
- CP:
-
Caudo-Putamen
- CTX:
-
Cortex
- EAE:
-
Experimental Autoimmune Encephalomyelitis
- GFAP:
-
Glial Fibrillary Acidic Protein
- GFP:
-
Green Fluorescence Protein
- GPCR:
-
G Protein-Coupled Receptor
- HDAC1/2:
-
Histone Deacetylase 1 and 2
- IRES:
-
Internal Ribosome Entry Site
- LCC:
-
Lateral Corpus Callosum,
- LFB:
-
Luxol Fast Blue
- MBP:
-
Myelin Basic Protein
- MCC:
-
Medial Corpus Callosum
- MS:
-
Multiple Sclerosis
- NG2:
-
Neural/Glial Antigen
- OPCs:
-
Oligodendrocyte Progenitor Cells
- QLIPP:
-
Quantitative Label-free Imaging with Phase and Polarization
- S1P:
-
Sphingosine-1-Phosphate
- S1pr1 :
-
S1P receptor 1 gene
- S1P1 :
-
S1P receptor 1
- S1PR1-5 :
-
Sphingosine-1-phosphate receptors 1–5
- SVZ:
-
Subventricular Zone
- TEV:
-
Tobacco Etch Virus
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We thank our colleagues Nora Sandrine Wetzel and Anna Tomczak for manuscript critical review.
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This study was supported by Foundation Leducq and a training grant from National Institutes of Health on infection, Immunity, and Inflammation (T32 AI 7290–32).
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EH: designed and performed the experiments, analyzed, and interpreted the data, made figures, and wrote the manuscript. EY performed IHC experiments, imaging, helped make figures, and did cell counting. H-CT performed EAE experiments and helped in flowcytometry tests and analysis. MM collaborated in tissue collection and data acquisition. LHY and SBM analyzed myelin by label-free imaging. MK and RP provided S1P1-GFP-signaling mice and contributed to the final manuscript. MH.H designed the experiments, analyzed, and interpreted the data and supervised the study. All authors read and approved the final manuscript.
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Hashemi, E., Yoseph, E., Tsai, HC. et al. Visualizing Sphingosine-1-Phosphate Receptor 1(S1P1) Signaling During Central Nervous System De- and Remyelination. Cell Mol Neurobiol 43, 1219–1236 (2023). https://doi.org/10.1007/s10571-022-01245-0
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DOI: https://doi.org/10.1007/s10571-022-01245-0