Cell surface levels of endothelial ICAM-1 influence the transcellular or paracellular T-cell diapedesis across the blood-brain barrier
Cell surface levels of endothelial ICAM-1 influence the transcellular or paracellular T-cell diapedesis across the blood-brain barrier
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DOI：
10.1002/eji.201445125
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发表时间：
2015-04-01
影响因子：
5.4
通讯作者：
Lyck, Ruth
中科院分区：
文献类型：
--
作者：
Abadier, Michael;Jahromi, Neda Haghayegh;Lyck, Ruth
CD 4（+）效应/记忆T细胞（T-EM细胞）跨血脑屏障（BBB）外渗是实验性自身免疫性脑脊髓炎（EAE）或多发性硬化（MS）发病机制中的关键步骤。内皮细胞ICAM-1和ICAM-2是CD 4 + T-EM细胞在血脑屏障上爬行的必要条件。在此，我们研究了细胞表面内皮细胞间粘附分子-1水平在确定生理流动下CD 4（+）T-EM细胞通过细胞因子处理的原代小鼠血脑屏障内皮细胞渗出的细胞途径中的影响。炎症条件下，诱导高水平的内皮细胞间粘附分子-1，促进CD 4（+）T细胞跨血脑屏障的跨细胞渗出的快速启动，而中等水平的内皮细胞间粘附分子-1有利于细胞旁的CD 4（+）T细胞渗出。重要的是，T细胞渗出穿过BBB的途径与BBB屏障性质的丧失无关。出乎意料的是，在内皮细胞ICAM-1和ICAM-2不存在的情况下，发现少量的CD 4（+）T-EM细胞通过明显的交替调节的跨细胞途径穿过发炎的BBB。在体内，这转化为ICAM-1（null）//ICAM-2（-/-）C57 BL/6 J小鼠中EAE的改善。总之，我们的研究表明，细胞表面水平的内皮细胞间粘附分子-1，而不是炎症刺激或血脑屏障的完整性影响的途径T细胞渗出血脑屏障。
The extravasation of CD4(+) effector/memory T cells (T-EM cells) across the blood-brain barrier (BBB) is a crucial step in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) or multiple sclerosis (MS). Endothelial ICAM-1 and ICAM-2 are essential for CD4(+) T-EM cell crawling on the BBB prior to diapedesis. Here, we investigated the influence of cell surface levels of endothelial ICAM-1 in determining the cellular route of CD4(+) T-EM-cell diapedesis across cytokine treated primary mouse BBB endothelial cells under physiological flow. Inflammatory conditions, inducing high levels of endothelial ICAM-1, promoted rapid initiation of transcellular diapedesis of CD4(+) T cells across the BBB, while intermediate levels of endothelial ICAM-1 favored paracellular CD4(+) T-cell diapedesis. Importantly, the route of T-cell diapedesis across the BBB was independent of loss of BBB barrier properties. Unexpectedly, a low number of CD4(+) T-EM cells was found to cross the inflamed BBB in the absence of endothelial ICAM-1 and ICAM-2 via an obviously alternatively regulated transcellular pathway. In vivo, this translated to the development of ameliorated EAE in ICAM-1(null)//ICAM-2(-/-)C57BL/6J mice. Taken together, our study demonstrates that cell surface levels of endothelial ICAM-1 rather than the inflammatory stimulus or BBB integrity influence the pathway of T-cell diapedesis across the BBB.