MiR-126 and miR-126* regulate shear-resistant firm leukocyte adhesion to human brain endothelium.
MiR-126 and miR-126* regulate shear-resistant firm leukocyte adhesion to human brain endothelium.
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DOI：
10.1038/srep45284
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发表时间：
2017-03-30
影响因子：
4.6
通讯作者：
Romero IA
中科院分区：
文献类型：
--
作者：
Cerutti C;Edwards LJ;de Vries HE;Sharrack B;Male DK;Romero IA
白细胞与脑内皮细胞的黏附是血脑屏障的主要组成部分，在多发性硬化症(MS)等神经炎性疾病的发病机制中起着至关重要的作用。白细胞黏附主要由促炎性细胞因子如肿瘤坏死因子α和干扰素γ诱导的选择素、细胞黏附分子和趋化因子介导，但这一过程的调控尚不完全清楚。本研究探讨了在人脑内皮细胞系hCMEC/D3中，受肿瘤坏死因子α和干扰素γ下调的两种不同的脑内皮细胞microRNAs(miR-126和miR-126*)对白细胞与脑内皮细胞牢固黏附的调节。利用体外模拟血流剪切力的白细胞黏附实验，我们观察到内皮细胞miR-126和miR-126*的减少增强了单核细胞和T细胞与hCMEC/D3细胞的牢固黏附，而它们的表达增加部分地阻止了THP1、Jurkat和MS患者原发PBMC的牢固黏附。此外，我们观察到miR-126*和miR-126下调分别增加了E-选择素和VCAM1，而miR-126过表达则降低了hCMEC/D3细胞VCAM1和CCL2的表达，提示这些miR通过调节黏附相关内皮mRNA靶标的表达来调节白细胞的黏附。因此，人脑内皮细胞miR-126和miR-126*可作为减少白细胞黏附从而减少神经炎症的治疗工具。
Leukocyte adhesion to brain endothelial cells, the blood-brain barrier main component, is a critical step in the pathogenesis of neuroinflammatory diseases such as multiple sclerosis (MS). Leukocyte adhesion is mediated mainly by selectins, cell adhesion molecules and chemokines induced by pro-inflammatory cytokines such as TNFα and IFNγ, but the regulation of this process is not fully clear. This study investigated the regulation of firm leukocyte adhesion to human brain endothelium by two different brain endothelial microRNAs (miRs), miR-126 and miR-126*, that are downregulated by TNFα and IFNγ in a human brain endothelial cell line, hCMEC/D3. Using a leukocyte adhesion in vitro assay under shear forces mimicking blood flow, we observed that reduction of endothelial miR-126 and miR-126* enhanced firm monocyte and T cell adhesion to hCMEC/D3 cells, whereas their increased expression partially prevented THP1, Jurkat and primary MS patient-derived PBMC firm adhesion. Furthermore, we observed that miR-126* and miR-126 downregulation increased E-selectin and VCAM1, respectively, while miR-126 overexpression reduced VCAM1 and CCL2 expression by hCMEC/D3 cells, suggesting that these miRs regulate leukocyte adhesion by modulating the expression of adhesion-associated endothelial mRNA targets. Hence, human brain endothelial miR-126 and miR-126* could be used as a therapeutic tool to reduce leukocyte adhesion and thus reduce neuroinflammation.