Role of sphingosine-1-phosphate receptor 2 (S1PR2) in demyelinating disease

Multiple sclerosis and other demyelinating diseases of the central nervous system (CNS) lead to diffused sites of blood-brain barrier (BBB) disruption, focal inflammation, myelin damage. Here, we report that sphingosine-1-phosphate receptor 2 (S1PR2) contribute in the process of demyelination and has a negative role in myelin repair mainly by modulating BBB permeability. Lysolecithin was used to induce demyelination in spinal cord dorsal column or optic chiasm of mice. In order to see the effect of S1PR2 inactivation on demyelination in inflammatory condition, experimental autoimmune encephalitis (EAE) was induced by MOG-peptide. In lysolecithin-induced demyelination of adult mouse spinal cord, S1PR2 inactivation by either the pharmacological inhibitor JTE-013 or S1PR2 gene knockout led to enhanced myelin repair as determined by higher numbers of differentiated oligodendrocytes and increased numbers of remyelinated axons at the lesion sites. S1PR2 inactivation in lysolecithin-induced demyelination of the optic chiasm, enhanced oligodendrogenesis and improved the behavioral outcome in an optokinetic reflex test. S1PR2 inhibition or knockout decreased the extent of demyelinated areas as well as the clinical disability in this EAE model. Both toxin induced and EAE models showed decreased BBB leakage and reduced numbers of Iba1+ macrophages following S1PR2 inactivation. Our results suggest that S1PR2 activity impairs remyelination and also enhances BBB leakage and demyelination. The former effect could be mediated by Nogo-A, as antagonism of this factor enhances remyelination and S1PR2 can act as a Nogo-A receptor.