Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, 77843.
Lipidomics Center, Medical University of South Carolina, Charleston, South Carolina, 29425.
Glia. 2018 Mar;66(3):654-669. doi: 10.1002/glia.23272. Epub 2017 Nov 29.
Recent evidence suggests that the oral drug Fingolimod (FTY720) for relapsing-remitting multiple sclerosis (MS) may act directly on the central nervous system (CNS) and modulate disease pathogenesis and progression in experimental models of MS. However, the specific subtype of sphingosine-1-phosphate (S1P) receptors that mediates the effect of FTY720 on the CNS cells has not been fully elucidated. Here, we report that S1P receptor 1 (S1PR1) is elevated in reactive astrocytes in an autoimmunity independent mouse model of MS and that selective S1PR1 modulation is sufficient to ameliorate the loss of oligodendrocytes and demyelination. The non-selective S1PR modulator, FTY720, or a short-lived S1PR1-specific modulator, CYM5442, was administered daily to mice while on cuprizone diet. Both FTY720- and CYM5422-treated mice displayed a significant reduction in oligodendrocyte apoptosis and astrocyte and microglial activation in comparison to vehicle-treated groups, which was associated with decreased production of proinflammatory mediators and down-regulation of astrocytic S1PR1 protein. Interestingly, S1PR1 modulation during the early phase of cuprizone intoxication was required to suppress oligodendrocyte death and consequent demyelination as drug treatment from 10 days after the initiation of cuprizone feeding was no longer effective. CYM5442 treatment during the brief cuprizone exposure significantly prevented Il-1β, Il-6, Cxcl10, and Cxcl3 induction, resulting in suppression of subsequent reactive gliosis and demyelination. Our study identifies functional antagonism of S1PR1 as a major mechanism for the protective effect of FTY720 in the cuprizone model and suggests pathogenic contributions of astrocyte S1PR1 signaling in primary demyelination and its potential as a therapeutic target for CNS inflammation.
最近的证据表明，用于治疗复发缓解型多发性硬化症（MS）的口服药物芬戈莫德（FTY720）可能直接作用于中枢神经系统（CNS），并在 MS 的实验模型中调节疾病的发病机制和进展。然而，介导 FTY720 对 CNS 细胞作用的鞘氨醇-1-磷酸（S1P）受体的特定亚型尚未完全阐明。在这里，我们报告 S1P 受体 1（S1PR1）在自身免疫性独立的 MS 小鼠模型中的反应性星形胶质细胞中升高，并且选择性 S1PR1 调节足以改善少突胶质细胞的丢失和脱髓鞘。非选择性 S1PR 调节剂 FTY720 或短寿命 S1PR1 特异性调节剂 CYM5442 在杯状蛋白饮食期间每天给予小鼠。与载体处理组相比，FTY720 和 CYM5422 处理的小鼠均显示出少突胶质细胞凋亡以及星形胶质细胞和小胶质细胞激活的显著减少，这与促炎介质产生减少和星形胶质细胞 S1PR1 蛋白下调有关。有趣的是，在杯状蛋白中毒的早期阶段调节 S1PR1 是抑制少突胶质细胞死亡和随后脱髓鞘所必需的，因为从杯状蛋白喂养开始后 10 天开始的药物治疗不再有效。在短暂的杯状蛋白暴露期间用 CYM5442 治疗可显著预防 Il-1β、Il-6、Cxcl10 和 Cxcl3 的诱导，从而抑制随后的反应性神经胶质增生和脱髓鞘。我们的研究确定了 S1PR1 的功能拮抗作用是 FTY720 在杯状蛋白模型中保护作用的主要机制，并表明星形胶质细胞 S1PR1 信号在原发性脱髓鞘及其作为 CNS 炎症治疗靶点的潜在作用。
