Fingolimod targets cerebral endothelial activation to block leukocyte recruitment in the central nervous system
Fingolimod targets cerebral endothelial activation to block leukocyte recruitment in the central nervous system
复制标题
芬戈莫德靶向脑内皮激活，阻止中枢神经系统中白细胞的募集
DOI：
10.1002/jlb.3a0717-287r
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发表时间：
2018
影响因子：
5.5
通讯作者：
Zhou Hong
中科院分区：
文献类型：
--
作者：
Zhao Yawei;Shi Dongyan;Cao Kelei;Wu Fengjiao;Zhu Xingxing;Wen Shuang;You Qiang;Zhang Keqi;Liu Lixin;Zhou Hong
Fingolimod（FTY 720）是一种免疫调节剂，被批准作为复发型多发性硬化症患者的口服治疗药物。其作用主要归因于其选择性地将淋巴细胞保留在淋巴结中以减少CNS中自身反应性T细胞募集的机制。在这项研究中，我们研究了FTY 720对脑室内注射LPS诱导的CNS炎症动物模型的治疗作用。我们发现FTY 720治疗通过抑制脑微血管中的白细胞募集来显著防止CNS中LPS诱导的中性粒细胞募集。此外，FTY 720还抑制脑内皮细胞上粘附分子的表达，但不影响CNS实质中促炎细胞因子（TNF-α和IL-6）和趋化因子（CXCL 1和CXCL 2）的表达水平。内皮激活的抑制伴随着信号分子磷酸化的减少，包括丝氨酸/苏氨酸特异性蛋白激酶（Akt）、STAT 6和核因子-κB。这种FTY 720减弱的白细胞募集和内皮激活抑制作用可通过阻断鞘氨醇激酶2或鞘氨醇-1-磷酸受体1的功能而逆转。我们的研究首次证明，FTY 720直接抑制内皮细胞中多种信号分子的磷酸化，从而有效地阻断CNS中白细胞的募集。
Fingolimod (FTY720), an immunomodulator, is approved as an oral treatment for patients with relapsing forms of multiple sclerosis. Its effects are largely attributed to its mechanism of selectively retaining lymphocytes in the lymph nodes to reduce autoreactive T‐cell recruitment in the CNS. In this study, we investigated the therapeutic effect of FTY720 on an animal model of CNS inflammation induced by intracerebral ventricle LPS injection. We found that FTY720 treatment significantly prevented LPS‐induced neutrophil recruitment in the CNS by inhibiting leukocyte recruitment in cerebral microvessels. Furthermore, FTY720 also inhibited the expressions of adhesion molecules on the cerebral endothelium, but did not affect the expression levels of pro‐inflammatory cytokines (TNF‐α and IL‐6) and chemokines (CXCL1 and CXCL2) in the CNS parenchyma. The inhibition of endothelial activation was accompanied by reduced phosphorylation of signaling molecules, including serine/threonine‐specific protein kinase (Akt), STAT6, and nuclear factor‐κB. This FTY720‐attenuated inhibition of leukocyte recruitment and endothelial activation was reversed by blocking the functions of sphingosine kinase 2 or sphingosine‐1‐phosphate receptor 1. Our study demonstrated, for the first time, that FTY720 directly inhibits the phosphorylation of multiple signaling molecules in endothelial cells, thereby effectively blocking leukocyte recruitment in the CNS.