IL-33对缺血性脑损伤的缓解作用及机制研究

Ischemic stroke is a leading cause of death and disability worldwide, and it is considered that inflammation plays a significant role in the pathogenesis of ischemic stroke. T cells and their subsets play critical roles in inflammation-mediated brain injury, and the prior work has suggested that the imbalance between Th1 and Th2 and the imbalance between Th17 and Treg may critically contribute to stroke, which may be the potential targets for stroke management and functional recovery. As an inducer of Th2 immune responses, Interleukin-33 (IL-33), a novel member of the IL-1 cytokine family, may have a role in regulating pathophysiology and inflammatory responses in the central nervous system. We have found that IL-33 may ameliorate ischemic brain injury in experimental stroke through promoting Th2 response and suppressing Th17 response. In this study, we'll further investigate the role of IL-33 and its signal pathway in ischemic brain injury, and the expression characteristics of IL-33 and its receptors. Additionally, the underlying mechanisms of IL-33 effects need to be further elucidated through detecting the Th1/Th2 and Th17/Treg balance, neuronal apoptosis and secretion, and microglial proliferation, phagocytosis and activation.

缺血性脑卒中是中老年人常见的脑血管疾病，免疫炎性反应在其发病机制中起着关键作用。T淋巴细胞及其亚群是缺血后炎症反应的重要参与者，研究表明，脑缺血后存在Th1/Th2和Th17/Treg细胞失衡，调节其失衡可能是治疗缺血性脑损伤的有效靶点。IL-1家族新成员IL-33是Th2型免疫反应的关键活化分子，其在调节中枢神经系统病理生理学和炎症应答过程中可能起着重要作用。我们在前期研究工作中初步发现，IL-33可缓解小鼠缺血性脑损伤，其效应与促进Th2应答和抑制Th17应答有关。本项目中，我们拟全面探讨IL-33及其信号通路在缺血性脑损伤中的作用，以及IL-33和其受体在脑缺血后的表达特征和意义，同时阐明IL-33对缺血性脑损伤的作用机制是否通过调控Th1/Th2、Th17/Treg细胞平衡以及影响神经元和胶质细胞功能来实现的。

缺血性脑卒中是中老年人常见的脑血管疾病，免疫炎性反应在其发病机制中起着关键作用。T淋巴细胞及其亚群是缺血后炎症反应的重要参与者，研究表明，脑缺血后存在Th1/Th2和Th17/Treg细胞失衡，调节其失衡可能是治疗缺血性脑损伤的有效靶点。IL-1家族新成员白细胞介素-33（IL-33）是Th2型免疫反应的关键活化分子，其在调节中枢神经系统病理生理学和炎症应答过程中可能起着重要作用。我们在前期研究中发现IL-33可缓解小鼠缺血性脑损伤。本项目中，我们在小鼠大脑中动脉栓塞模型和急性缺血性脑卒中患者的基础上，进一步探讨了IL-33及其信号通路在缺血性脑损伤中的作用和机制，以及IL-33和其受体在脑缺血后的表达特征和意义。我们研究发现在小鼠短暂性脑缺血模型IL-33/ST2信号通路被下调，其与sST2表达增多有关。而在急性缺血性脑卒中患者增高的血清sST2水平与脑梗死体积和NIHSS评分呈正相关，提示其可能作为一种新型炎性标志物辅助诊断和评价脑卒中的疾病严重程度。此外，我们还发现IL-33可抑制外周脾脏Th1型免疫反应和促进调节性T细胞（Treg）免疫反应，参与调节脾脏T细胞免疫反应。IL-33还能够促进缺血脑组织中Treg细胞的分化和增殖，然后表达AREG蛋白并分泌作用于EGFR，促进神经元再生和缓解缺血性脑损伤。由此可见，IL-33缓解缺血性脑损伤的作用机制主要是通过调控外周和中枢神经系统Treg细胞来实现的。IL-33/ST2信号通路可能是脑卒中免疫干预治疗的一个重要靶点，具有一定临床应用前景。