Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran; Brain Research Institute, University of Zurich, CH-8057 Zurich, Switzerland.
Brain Research Institute, University of Zurich, CH-8057 Zurich, Switzerland.
Neurobiol Dis. 2019 Apr;124:189-201. doi: 10.1016/j.nbd.2018.11.018. Epub 2018 Nov 22.
Multiple sclerosis is an inflammatory disease of the central nervous system (CNS) in which multiple sites of blood-brain barrier (BBB) disruption, focal inflammation, demyelination and tissue destruction are the hallmarks. Here we show that sphingosine-1-phosphate receptor 2 (S1PR2) has a negative role in myelin repair as well as an important role in demyelination by modulating BBB permeability. 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. In order to see the effect of S1PR2 inactivation on demyelination, experimental autoimmune encephalitis (EAE) was induced by MOG-peptide. 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.
多发性硬化症是一种中枢神经系统（CNS）的炎症性疾病，其特征是多个血脑屏障（BBB）破坏、局灶性炎症、脱髓鞘和组织破坏部位。在这里，我们表明，鞘氨醇-1-磷酸受体 2（S1PR2）在髓鞘修复中具有负作用，并且通过调节 BBB 通透性在脱髓鞘中具有重要作用。在成年小鼠脊髓中的溶血磷脂酰胆碱诱导的脱髓鞘中，通过药理学抑制剂 JTE-013 或 S1PR2 基因敲除使 S1PR2 失活，导致髓鞘修复增强，表现为分化的少突胶质细胞数量增加和病变部位的髓鞘再生轴突数量增加。在溶血磷脂酰胆碱诱导的视交叉脱髓鞘中 S1PR2 失活，增强了少突胶质细胞发生并改善了在视动反射测试中的行为结果。为了观察 S1PR2 失活对脱髓鞘的影响，通过 MOG-肽诱导实验性自身免疫性脑脊髓炎（EAE）。S1PR2 抑制或敲除减少了脱髓鞘区域的范围以及该 EAE 模型中的临床残疾。在这两种毒素诱导和 EAE 模型中，S1PR2 失活后 BBB 渗漏减少，Iba1 巨噬细胞数量减少。我们的结果表明，S1PR2 活性会损害髓鞘修复，并且还会增强 BBB 渗漏和脱髓鞘。前一种作用可能是由 Nogo-A 介导的，因为拮抗该因子可增强髓鞘修复，并且 S1PR2 可以作为 Nogo-A 受体。
