Fingolimod prevents blood-brain barrier disruption induced by the sera from patients with multiple sclerosis.
Fingolimod prevents blood-brain barrier disruption induced by the sera from patients with multiple sclerosis.
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DOI：
10.1371/journal.pone.0121488
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Kanda T
中科院分区：
文献类型：
--
作者：
Nishihara H;Shimizu F;Sano Y;Takeshita Y;Maeda T;Abe M;Koga M;Kanda T
芬戈莫德在多发性硬化症（MS）中的作用被认为涉及防止淋巴细胞从淋巴组织中流出，从而减少穿过血脑屏障（BBB）进入中枢神经系统的自身攻击性淋巴细胞浸润。然而，脑微血管内皮细胞（BMEC）通过直接修复BBB的功能，代表了MS患者中芬戈莫德的可能的额外靶点，因为BMEC也表达S1 P受体。在这项研究中，我们评估了芬戈莫德对BMEC的影响，并阐明了芬戈莫德-磷酸盐暴露于MS血清后是否能恢复BBB功能。在含或不含芬戈莫德/磷酸芬戈莫德的条件培养基中孵育后，评价BMEC中紧密连接蛋白、粘附分子和跨内皮电阻（TEER）的变化。此外，评估了在存在芬戈莫德-磷酸盐的情况下，MS患者（包括复发缓解型（RR）MS复发期、RRMS稳定期和继发性进展型MS（SPMS）患者）血清对BBB功能的影响。与磷酸芬戈莫德一起孵育增加了BMEC中的claudin-5蛋白水平和TEER值，尽管它没有改变occludin、ICAM-1或MelCAM蛋白的量。用磷酸芬戈莫德预处理恢复了暴露于MS血清后BMEC中claudin-5和VCAM-1蛋白/mRNA水平和TEER值的变化。磷酸芬戈莫德预处理可通过上调BMEC中的claudin-5和下调VCAM-1来防止RRMS和SPMS血清引起的BBB破坏，表明磷酸芬戈莫德能够直接修饰BBB。BMEC代表MS患者中芬戈莫德的可能治疗靶点。
Effect of fingolimod in multiple sclerosis (MS) is thought to involve the prevention of lymphocyte egress from lymphoid tissues, thereby reducing autoaggressive lymphocyte infiltration into the central nervous system across blood-brain barrier (BBB). However, brain microvascular endothelial cells (BMECs) represent a possible additional target for fingolimod in MS patients by directly repairing the function of BBB, as S1P receptors are also expressed by BMECs. In this study, we evaluated the effects of fingolimod on BMECs and clarified whether fingolimod-phosphate restores the BBB function after exposure to MS sera. Changes in tight junction proteins, adhesion molecules and transendothelial electrical resistance (TEER) in BMECs were evaluated following incubation in conditioned medium with or without fingolimod/fingolimod-phosphate. In addition, the effects of sera derived from MS patients, including those in the relapse phase of relapse-remitting (RR) MS, stable phase of RRMS and secondary progressive MS (SPMS), on the function of BBB in the presence of fingolimod-phosphate were assessed. Incubation with fingolimod-phosphate increased the claudin-5 protein levels and TEER values in BMECs, although it did not change the amount of occludin, ICAM-1 or MelCAM proteins. Pretreatment with fingolimod-phosphate restored the changes in the claudin-5 and VCAM-1 protein/mRNA levels and TEER values in BMECs after exposure to MS sera. Pretreatment with fingolimod-phosphate prevents BBB disruption caused by both RRMS and SPMS sera via the upregulation of claudin-5 and downregulation of VCAM-1 in BMECs, suggesting that fingolimod-phosphate is capable of directly modifying the BBB. BMECs represent a possible therapeutic target for fingolimod in MS patients.
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