Sphingosine 1 Phosphate at the Blood Brain Barrier: Can the Modulation of S1P Receptor 1 Influence the Response of Endothelial Cells and Astrocytes to Inflammatory Stimuli?
Sphingosine 1 Phosphate at the Blood Brain Barrier: Can the Modulation of S1P Receptor 1 Influence the Response of Endothelial Cells and Astrocytes to Inflammatory Stimuli?
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DOI：
10.1371/journal.pone.0133392
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Ransohoff RM
中科院分区：
文献类型：
--
作者：
Spampinato SF;Obermeier B;Cotleur A;Love A;Takeshita Y;Sano Y;Kanda T;Ransohoff RM
血脑屏障（BBB）维持正常屏障功能、维持中枢神经系统（CNS）活动的最佳环境和调节白细胞进入的能力在CNS疾病中会受到影响。内皮细胞和星形胶质细胞是血脑屏障的主要细胞成分，它们之间的相互作用对维持血脑屏障的功能至关重要。内皮细胞和星形胶质细胞都表达生物活性鞘脂S1 P的受体。Fingolimod是一种免疫调节药物，其结构与S1 P相似，已被批准用于治疗多发性硬化症（MS）：Fingolimod通过防止淋巴结中的白细胞流出来降低MS复发率。在这里，我们检查了S1 P和芬戈莫德作用于BBB的能力，使用体外共培养模型，使我们能够研究S1 P对内皮细胞，星形胶质细胞的影响，以及两者之间的相互作用。选择性作用于内皮细胞，S1 P受体信号减少由炎性细胞因子诱导的细胞死亡。当作用于星形胶质细胞时，芬戈莫德治疗诱导释放一种因子，即粒细胞巨噬细胞集落刺激因子（GM-CSF），该因子可降低细胞因子对内皮细胞的影响。在体外BBB模型中，结合剪切应力，S1 P受体调节减少了白细胞穿过内皮屏障的迁移，表明可能有助于芬戈莫德治疗MS疗效的新机制。
The ability of the Blood Brain Barrier (BBB) to maintain proper barrier functions, keeping an optimal environment for central nervous system (CNS) activity and regulating leukocytes’ access, can be affected in CNS diseases. Endothelial cells and astrocytes are the principal BBB cellular constituents and their interaction is essential to maintain its function. Both endothelial cells and astrocytes express the receptors for the bioactive sphingolipid S1P. Fingolimod, an immune modulatory drug whose structure is similar to S1P, has been approved for treatment in multiple sclerosis (MS): fingolimod reduces the rate of MS relapses by preventing leukocyte egress from the lymph nodes. Here, we examined the ability of S1P and fingolimod to act on the BBB, using an in vitro co-culture model that allowed us to investigate the effects of S1P on endothelial cells, astrocytes, and interactions between the two. Acting selectively on endothelial cells, S1P receptor signaling reduced cell death induced by inflammatory cytokines. When acting on astrocytes, fingolimod treatment induced the release of a factor, granulocyte macrophage colony-stimulating factor (GM-CSF) that reduced the effects of cytokines on endothelium. In an in vitro BBB model incorporating shear stress, S1P receptor modulation reduced leukocyte migration across the endothelial barrier, indicating a novel mechanism that might contribute to fingolimod efficacy in MS treatment.