Remote Limb Ischemic Postconditioning Protects Against Ischemic Stroke by Promoting Regulatory T Cells Thriving.
Remote Limb Ischemic Postconditioning Protects Against Ischemic Stroke by Promoting Regulatory T Cells Thriving.
复制标题
远端肢体缺血后处理通过促进调节性 T 细胞繁荣来预防缺血性中风
DOI：
10.1161/jaha.121.023077
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发表时间：
2021-11-16
影响因子：
5.4
通讯作者：
Tian DS
中科院分区：
文献类型：
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作者：
Yu HH;Ma XT;Ma X;Chen M;Chu YH;Wu LJ;Wang W;Qin C;Tian DS
远程肢体缺血后处理(RLIPoC)已被证明对缺血性卒中具有保护作用。然而，RLIPoC介导跨器官保护的潜在机制仍未完全阐明。采用大脑中动脉闭塞60min复制缺血性卒中模型。大脑中动脉再灌注后即刻行RLIPoC，缺血10min，双侧股动脉再灌流10min。用流式细胞仪检测脾、血和脑中调节性T细胞(Tregs)的百分比，并使用带有增强型绿色荧光蛋白标记的Foxp3的转基因小鼠计算缺血侧Tregs的数量。此外，利用多光谱光学成像系统动态监测代谢状态。在注射白喉毒素后，Treg转基因小鼠的Treg被有条件地耗尽。免疫荧光染色观察炎症反应和神经细胞凋亡情况。分别使用磁共振成像和改良的神经严重程度评分评估脑梗塞体积和神经功能缺陷。结果表明，RLIPoC显著缩小了脑梗塞体积，改善了神经功能，显著增加了脾、血和缺血半球的Tregs。在RLIPoC之后，代谢物，如黄素腺嘌呤二核苷酸和烟酰胺腺嘌呤二核苷酸水合物，在RLIPoC传导的局部组织和循环血液中随后发生变化。此外，烟酰胺腺嘌呤二核苷酸水合物可模拟RLIPoC增加Tregs。相反，使用Treg小鼠的耗尽来耗尽Treg的Treg会损害RLIPoC所赋予的神经保护作用。RLIPoC对缺血性脑损伤有保护作用，至少部分是通过烟酰胺腺嘌呤二核苷酸/烟酰胺腺嘌呤二核苷酸水合物途径激活和维持Tregs。
Remote limb ischemic postconditioning (RLIPoC) has been demonstrated to protect against ischemic stroke. However, the underlying mechanisms of RLIPoC mediating cross‐organ protection remain to be fully elucidated. Ischemic stroke was induced by middle cerebral artery occlusion for 60 minutes. RLIPoC was performed with 3 cycles of 10‐minute ischemia followed by 10‐minute reperfusion of the bilateral femoral arteries immediately after middle cerebral artery reperfusion. The percentage of regulatory T cells (Tregs) in the spleen, blood, and brain was detected using flow cytometry, and the number of Tregs in the ischemic hemisphere was counted using transgenic mice with an enhanced green fluorescent protein‐tagged Foxp3. Furthermore, the metabolic status was monitored dynamically using a multispectral optical imaging system. The Tregs were conditionally depleted in the depletion of Treg transgenic mice after the injection of the diphtheria toxin. The inflammatory response and neuronal apoptosis were investigated using immunofluorescent staining. Infarct volume and neurological deficits were evaluated using magnetic resonance imaging and the modified neurological severity score, respectively. The results showed that RLIPoC substantially reduced infarct volume, improved neurological function, and significantly increased Tregs in the spleen, blood, and ischemic hemisphere after middle cerebral artery occlusion. RLIPoC was followed by subsequent alteration in metabolites, such as flavin adenine dinucleotide and nicotinamide adenine dinucleotide hydrate, both in RLIPoC‐conducted local tissues and circulating blood. Furthermore, nicotinamide adenine dinucleotide hydrate can mimic RLIPoC in increasing Tregs. Conversely, the depletion of Tregs using depletion of Treg mice compromised the neuroprotective effects conferred by RLIPoC. RLIPoC protects against ischemic brain injury, at least in part by activating and maintaining the Tregs through the nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide hydrate pathway.