Cellular mechanisms of IL-17-induced blood-brain barrier disruption
Cellular mechanisms of IL-17-induced blood-brain barrier disruption
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DOI：
10.1096/fj.09-141978
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发表时间：
2010-04-01
期刊：
影响因子：
4.8
通讯作者：
Kuhlmann, Christoph R. W.
中科院分区：
文献类型：
--
作者：
Huppert, Jula;Closhen, Dorothea;Kuhlmann, Christoph R. W.
最近，T辅助17（Th 17）细胞被证明通过IL-17 A的作用破坏血脑屏障（BBB）。本研究的目的是研究IL-17 A诱导的血脑屏障破坏的机制。在小鼠脑内皮细胞系弯曲中分析屏障完整性。3通过使用电呼叫阻抗感测技术测量电阻值。此外，进行细胞内蛋白质印迹、荧光成像、单核细胞粘附和跨内皮迁移测定。在C57 BL/6小鼠中诱导实验性自身免疫性脑脊髓炎（EAE）。IL-17 A诱导NADPH氧化酶或黄嘌呤氧化酶依赖性活性氧（ROS）的产生。由此产生的氧化应激激活内皮收缩机制，这是伴随着紧密连接分子occludin的下调。阻断ROS形成或肌球蛋白轻链磷酸化或应用IL-17 A-中和抗体可防止IL-17 A诱导的BBB破坏。使用ML-7（一种肌球蛋白轻链激酶抑制剂）治疗EAE小鼠，导致脊髓BBB破坏减少，淋巴细胞通过BBB浸润减少，随后降低了EAE的临床特征。这些观察结果表明，IL-17 A通过损害BBB的完整性，涉及ROS的增加产生，在EAE的发展中起着关键作用。Huppert，J.，Closhen，D.，Croxford，A.，白色，R，Kulig，P.，Pietrowski，E.，贝赫曼岛Becher，B.，卢曼，H。J.，Waisman，A.，库尔曼角R. W. IL-17诱导的血脑屏障破坏的细胞机制。FASEB J.24，1023-1034（2010）。www.fasebj.org
Recently T-helper 17 (Th17) cells were demonstrated to disrupt the blood-brain barrier (BBB) by the action of IL-17A. The aim of the present study was to examine the mechanisms that underlie IL-17A-induced BBB breakdown. Barrier integrity was analyzed in the murine brain endothelial cell line bEnd. 3 by measuring the electrical resistance values using electrical call impedance sensing technology. Furthermore, in-cell Western blots, fluorescence imaging, and monocyte adhesion and transendothelial migration assays were performed. Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice. IL-17A induced NADPH oxidase-or xanthine oxidase-dependent reactive oxygen species (ROS) production. The resulting oxidative stress activated the endothelial contractile machinery, which was accompanied by a down-regulation of the tight junction molecule occludin. Blocking either ROS formation or myosin light chain phosphorylation or applying IL-17A-neutralizing antibodies prevented IL-17A-induced BBB disruption. Treatment of mice with EAE using ML-7, an inhibitor of the myosin light chain kinase, resulted in less BBB disruption at the spinal cord and less infiltration of lymphocytes via the BBB and subsequently reduced the clinical characteristics of EAE. These observations indicate that IL-17A accounts for a crucial step in the development of EAE by impairing the integrity of the BBB, involving augmented production of ROS.-Huppert, J., Closhen, D., Croxford, A., White, R., Kulig, P., Pietrowski, E., Bechmann, I., Becher, B., Luhmann, H. J., Waisman, A., Kuhlmann, C. R. W. Cellular mechanisms of IL-17-induced blood-brain barrier disruption. FASEB J. 24, 1023-1034 (2010). www.fasebj.org