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-β (TGF-β). 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.

中文翻译：

---

调节性T细胞对于白介素33介导的中风神经保护至关重要。

已知白介素33（IL-33）激活调节性T淋巴细胞（Tregs），后者与缺血性中风后的脑损伤呈负相关。在这项研究中，我们旨在研究Treg在IL-33介导的神经保护中的作用，并阐明其潜在机制。在体内，对雄性C57BL / 6 N小鼠进行60分钟的短暂性脑中动脉闭塞（tMCAO），然后在受伤后立即每天给予媒介物或IL-33。通过腹膜内施用抗CD25抗体（抗CD25Ab）来消除Treg。在每组中研究行为改变，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，对原代小鼠神经元细胞进行氧葡萄糖剥夺（OGD）3小时。诱导缺氧时，将媒介物或药物调节的Tregs应用于神经元。在每组中测量神经元凋亡和细胞因子表达。结果表明，腹膜内给予抗CD25Ab可减少CD4 + CD25 + Foxp3 + Tregs，增加梗塞体积，增强中风诱发的细胞死亡和降低感觉运动功能。值得注意的是，IL-33会增加脾脏和大脑中的CD4 + CD25 + Foxp3 + Treg。然而，阻断ST2减弱了IL-33的这些作用。经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CD25Ab消除了IL-33的神经保护作用。机械上，IL-33的神经保护作用与凋亡相关蛋白的减少和Tregs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ST2依赖性调节性T细胞的扩增和活化，从而提供了针对缺血性脑损伤的神经保护作用，代表了治疗中风的有希望的免疫调节靶标。