C-C Chemokine Receptor Type 5 (CCR5)-Mediated Docking of Transferred Tregs Protects Against Early Blood-Brain Barrier Disruption After Stroke.
C-C Chemokine Receptor Type 5 (CCR5)-Mediated Docking of Transferred Tregs Protects Against Early Blood-Brain Barrier Disruption After Stroke.
复制标题
C-C 趋化因子受体 5 型 (CCR5) 介导的转移性 Tregs 对接可防止中风后早期血脑屏障破坏
DOI：
10.1161/jaha.117.006387
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发表时间：
2017-08-02
影响因子：
5.4
通讯作者：
Hu X
中科院分区：
文献类型：
--
作者：
Li P;Wang L;Zhou Y;Gan Y;Zhu W;Xia Y;Jiang X;Watkins S;Vazquez A;Thomson AW;Chen J;Yu W;Hu X
尽管最近的证据表明过继转移的调节性T细胞（Tcells）在缺血性中风中具有有效的保护作用，但值得注意的是，缺血性脑中Treg动员和活化的机制是未知的。这项研究确定了C-C趋化因子受体5型（CCR 5）在介导转移的TbR的对接和激活中的作用，以保护中风后早期血脑屏障破坏。连续转移CCR 5 −/− T细胞未能减少脑梗死或神经功能缺损，表明CCR 5在Treg中不可或缺的作用-提供了对脑缺血的保护。双光子实时成像表明，CCR 5对于Treg在受损血管壁的对接至关重要，在脑缺血损伤后，它们与血源性中性粒细胞/巨噬细胞相互作用。CCR 5缺乏对供体TCFs的影响，剥夺了它们对血脑屏障损伤的早期保护作用。使用流式细胞术，真实的时间聚合酶链反应，和免疫染色，我们证实了CCL 5的表达，一个CCR 5配体，在脑缺血后损伤的内皮细胞上显著升高，伴随着CCR 5上调循环TcR。在Treg-内皮细胞共培养物中，在暴露于缺血损伤的内皮细胞时，TcR 5在TcR上诱导表达。此外，TCR 5对TcB的诱导增强了抑制性分子程序性死亡配体1的表达，这反过来又抑制了中性粒细胞衍生的基质金属肽酶9。这些结果表明，CCR 5是Treg介导的血脑屏障保护的关键分子，也是优化Treg治疗中风的潜在靶点。
Despite recent evidence demonstrating a potent protective effect of adoptively transferred regulatory T cells (Tregs) in ischemic stroke, the mechanism for Treg mobilization and activation in the ischemic brain is, remarkably, unknown. This study determines the role of C‐C chemokine receptor type 5 (CCR5) in mediating the docking and activation of transferred Tregs in their protection of early blood‐brain barrier disruption after stroke. Adoptive transfer of CCR5−/− Tregs failed to reduce brain infarct or neurological deficits, indicating an indispensable role of CCR5 in Treg‐afforded protection against cerebral ischemia. Two‐photon live imaging demonstrated that CCR5 was critical for Treg docking at the injured vessel wall, where they interact with blood‐borne neutrophils/macrophages after cerebral ischemic injury. CCR5 deficiency on donor Tregs deprived of their early protection against blood‐brain barrier damage. Using flow cytometry, real‐time polymerase chain reaction, and immunostaining, we confirmed that the expression of CCL5, a CCR5 ligand, was significantly elevated on the injured endothelium after cerebral ischemia, accompanied by CCR5 upregulation on circulating Tregs. In a Treg‐endothelial cell coculture, CCR5 expression was induced on Tregs on their exposure to ischemia‐injured endothelial cells. Furthermore, CCR5 induction on Tregs enhanced expression of the inhibitory molecule programmed death ligand 1, which in turn inhibited neutrophil‐derived matrix metallopeptidase 9. These results suggest that CCR5 is a critical molecule for Treg‐mediated blood‐brain barrier protection and a potential target to optimize Treg therapy for stroke.