Human blood-brain barrier disruption by retroviral-infected lymphocytes: Role of myosin light chain kinase in endothelial tight-junction disorganization
Human blood-brain barrier disruption by retroviral-infected lymphocytes: Role of myosin light chain kinase in endothelial tight-junction disorganization
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DOI：
10.4049/jimmunol.179.4.2576
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发表时间：
2007-08-15
影响因子：
4.4
通讯作者：
Ceccaldi, Pierre-Emmanuel
中科院分区：
文献类型：
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作者：
Afonso, Philippe Vicente;Ozden, Simona;Ceccaldi, Pierre-Emmanuel
血脑屏障（131313）构成血液和脑实质之间的界面，已被证明在逆转录病毒相关的神经脊髓病期间被破坏。人T细胞白血病病毒（HTLV-1）相关性脊髓病/热带痉挛性轻瘫是一种缓慢进行性神经退行性疾病，其中BBB破坏的证据已通过CNS中存在淋巴细胞浸润和血浆蛋白通过脑内皮渗漏得到证实。使用体外人血脑屏障模型，我们研究了HTLV-1感染的淋巴细胞诱导的内皮细胞变化的细胞和分子机制。我们证明，与感染的淋巴细胞共培养诱导增加细胞旁内皮通透性和跨细胞迁移，通过IL-1 α和TNF-α分泌。这种破坏与内皮细胞之间的紧密连接紊乱以及紧密连接蛋白如闭合小带1的表达模式的改变有关。这些变化可以通过抑制NF-κ B通路或肌球蛋白轻链激酶活性来预防。在HTLV-1相关性脊髓病/热带痉挛性下肢轻瘫患者的脊髓组织切片中证实了这种紊乱。基于这种BBB模型，目前的数据表明，HTLV-1感染的淋巴细胞可以诱导BBB破坏，并可能是负责CNS浸润，发生在逆转录病毒相关的神经脊髓病的早期步骤。
The blood-brain barrier (131313), which constitutes the interface between blood and cerebral parenchyma, has been shown to be disrupted during retroviral associated neuromyelopathies. Human T cell leukemia virus (HTLV-1)-associated myelopathy/tropical spastic paraparesis is a slowly progressive neurodegenerative disease, in which evidence of BBB breakdown has been demonstrated by the presence of lymphocytic infiltrates in the CNS and plasma protein leakage through cerebral endothelium. Using an in vitro human BBB model, we investigated the cellular and molecular mechanisms involved in endothelial changes induced by HTLV-1-infected lymphocytes. We demonstrate that coculture with infected lymphocytes induces an increase in paracellular endothelial permeability and transcellular migration, via IL-1 alpha and TNF-alpha secretion. This disruption is associated with tight junction disorganization between endothelial cells, and alterations in the expression pattern of tight junction proteins such as zonula occludens 1. These changes could be prevented by inhibition of the NF-kappa B pathway or of myosin light chain kinase activity. Such disorganization was confirmed in histological sections of spinal cord from an HTLV-1-associated myelopathy/tropical spastic paraparesis patient. Based on this BBB model, the present data indicate that HTLV-1-infected lymphocytes can induce BBB breakdown and may be responsible for the CNS infiltration that occurs in the early steps of retroviral-associated neuromyelopathies.