Adhesion and migration of polymorphonuclear leukocytes across human brain microvessel endothelial cells are differentially regulated by endothelial cell adhesion molecules and modulate monolayer permeability
Adhesion and migration of polymorphonuclear leukocytes across human brain microvessel endothelial cells are differentially regulated by endothelial cell adhesion molecules and modulate monolayer permeability
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DOI：
10.1016/j.jneuroim.2006.12.003
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发表时间：
2007-03-01
影响因子：
3.3
通讯作者：
Dorovini-Zis, Katerina
中科院分区：
文献类型：
--
作者：
Wong, Donald;Prameya, Rukmini;Dorovini-Zis, Katerina
多形核白细胞（PMN）穿过人血脑屏障的机制尚未完全阐明。使用一个很好的特点，在体外模型的人血脑屏障，我们研究的作用，内皮细胞粘附分子的粘附和跨内皮细胞迁移的中性粒细胞在原代培养的人脑微血管内皮细胞（HBMEC）。少数PMN（0.06%）粘附于未刺激的HBMEC，其基础粘附不受抗粘附分子抗体的影响。用肿瘤坏死因子（TNF）-α治疗HBMEC导致PMN粘附增加，这被E-选择素和ICAM-1的阻断抗体显著抑制，但不被VCAM-1或PECAM-1抑制。极少数粘附的PMN迁移穿过未刺激的HBMEC单层。用TNF-α刺激HBMEC后，迁移增加2至20倍。单克隆抗体阻断研究表明，PMN使用ICAM-1，而不是VCAM-1，E-选择素或PECAM-I移动穿过活化的单层。抗粘附分子抗体并没有减少基础PMN迁移。超微结构上，中性粒细胞常聚集于内皮细胞顶部和相邻内皮细胞之间，并沿内皮细胞顶端表面沿着延伸伪足粘附。然后，它们变平并插入内皮细胞之间，以便穿过单层迁移。在迁移期结束时，文化恢复了连续性，没有中断的迹象。中性粒细胞的跨内皮迁移降低了跨内皮电阻，并增加了辣根过氧化物酶的渗透性，它渗透在迁移的白细胞旁边。ICAM-1的阻断抗体大大降低了迁移，但对通透性变化没有影响。这些研究提供了对调节PMN进入大脑和CNS炎症中BBB通透性增加的机制的见解。(c)2006 Elsevier B. V.保留所有权利。
The mechanisms by which polymorphonuclear leukocytes (PMN) cross the human blood-brain barrier have not been fully elucidated. Using a well characterized in vitro model of the human BBB, we examined the role of endothelial cell adhesion molecules on the adhesion and transendothelial migration of PMN across primary cultures of human brain microvessel endothelial cells (HBMEC). A small number of PMN (0.06%) adhered to unstimulated HBMEC, and the basal adhesion was not affected by anti-adhesion molecule antibodies. Treatment of HBMEC with tumor necrosis factor (TNF)-alpha resulted in increased PMN adhesion that was significantly inhibited by blocking antibodies to E-selectin and ICAM-1, but not VCAM-1 or PECAM-1. A very small number of adherent PMN migrated across unstimulated HBMEC monolayers. Migration increased 2 to 20 fold following stimulation of HBMEC with TNF-alpha. Monoclonal antibody blocking studies showed that PMN used ICAM-1, but not VCAM-1, E-selectin or PECAM-I to move across activated monolayers. Anti-adhesion molecule antibodies did not diminish the basal PMN migration. Ultrastructurally, PMN often aggregated on top and between adjacent endothelial cells and adhered by first extending pseudopodia along the apical endothelial surface. They then flattened and inserted themselves between endothelial cells in order to migrate across the monolayers. At the end of the migration period, the cultures resumed their continuity with no evidence of disruption. Transendothelial migration of PMN decreased the transendothelial electrical resistance and increased the permeability to horseradish peroxidase, which penetrated alongside the migrating leukocytes. A blocking antibody to ICAM-1 that greatly decreased migration, had no effect on the permeability changes. These studies provide insights into the mechanisms that regulate the entry of PMN into the brain and the increased permeability of the BBB in CNS inflammation. (c) 2006 Elsevier B.V. All rights reserved.