Regulatory T cell is critical for interleukin-33-mediated neuroprotection against stroke
Regulatory T cell is critical for interleukin-33-mediated neuroprotection against stroke
复制标题
调节性 T 细胞对于白细胞介素 33 介导的中风神经保护至关重要
DOI：
10.1016/j.expneurol.2020.113233
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发表时间：
2020-06-01
影响因子：
5.3
通讯作者：
Song, Bo
中科院分区：
文献类型：
--
作者：
Liu, Xinjing;Hu, Ruiyao;Song, Bo
白细胞介素-33（IL-33）可激活调节性T淋巴细胞（Tlymphocyte，Tlymphocyte），Tlymphocyte与缺血性脑卒中后的脑损伤呈负相关。在这项研究中，我们的目的是调查的IL-33介导的神经保护中的作用，并阐明其潜在的机制。在体内，雄性C57 BL/6 N小鼠经受60分钟的短暂大脑中动脉闭塞（tMCAO），随后在损伤后立即每日施用媒介物或IL-33。通过腹膜内施用抗-CD 25抗体（抗-CD 25 Ab）来消耗T细胞。研究各组的行为变化、脑水肿、神经元损伤、Treg百分比和细胞因子表达水平。在体外实验中，原代小鼠神经元细胞经受氧-葡萄糖剥夺（OGD）3 h。在诱导缺氧时，将溶剂或药物调节的TdR应用于神经元。检测各组神经细胞凋亡和细胞因子表达。结果表明，腹膜内给予抗CD 25抗体降低了CD 4 + CD 25 + Foxp 3 + T细胞，增加了梗死体积，增强了卒中诱导的细胞死亡，并降低了感觉运动功能。值得注意的是，IL-33增加了脾和脑中的CD 4 + CD 25 + Foxp 3 + T细胞。然而，阻断ST 2减弱了IL-33的这些作用。IL-33处理的Treg培养物的上清液减少了神经元凋亡并提高了Treg细胞因子IL-10、IL-35和转化生长因子-β（TGF-β）的产生。抗CD 25抗体消除了IL-33的神经保护作用。从机制上讲，IL-33的神经保护作用与糖尿病相关蛋白的减少和T细胞相关细胞因子的产生有关。总体而言，这些发现表明，IL-33通过涉及抗凋亡蛋白和细胞因子的机制增强ST 2依赖性调节性T细胞扩增和活化，提供针对缺血性脑损伤的神经保护，代表了治疗中风的有希望的免疫调节靶点。
Interleukin-33 (IL-33) is known to activate the regulatory T lymphocytes (Tregs), which are negatively correlated with brain damage after ischemic stroke. In this study, we aimed to investigate the role of Tregs in IL-33-mediated neuroprotection and elucidate the underlying mechanisms. In vivo, male C57BL/6 N mice were subjected to 60 min of transient middle cerebral artery occlusion (tMCAO), followed by daily administration of vehicle or IL-33 immediately after injury. Tregs were depleted by intraperitoneal administration of anti-CD25 antibody (anti-CD25Ab). Behavioral changes, brain edema, neuronal injury, Treg percentages, and cytokine expression levels were investigated in each group. In vitro experiments, primary mouse neuronal cells were subjected to oxygen-glucose deprivation (OGD) for 3 h. Vehicle- or drug-conditioned Tregs were applied to the neurons at the time of induction of hypoxia. Neuronal apoptosis and cytokine expression were measured in each group. The results indicate that intraperitoneal administration of anti-CD25Ab reduced CD4 + CD25 + Foxp3+ Tregs, increased infarct volume, enhanced stroke-induced cell death, and decreased sensorimotor functions. Notably, IL-33 increased CD4 + CD25 + Foxp3+ Tregs in the spleen and brain. However, blockading ST2 attenuated these effects of IL-33. The supernatant of the IL-33-treated Treg culture reduced neuronal apoptosis and elevated the production of the Treg cytokines IL-10, IL-35, and transforming growth factor-beta (TGF-beta). Anti-CD25Ab abrogated the neuroprotective effect of IL-33. Mechanistically, the neuroprotective effects of IL-33 were associated with reduction in apoptosis-related proteins and production of Tregs related cytokines. Overall, these findings showed that IL-33 afforded neuroprotection against ischemic brain injury by enhancing ST2-dependent regulatory T-cell expansion and activation via a mechanism involving anti-apoptosis proteins and cytokines, representing a promising immune modulatory target for the treatment of stroke.