中枢神经系统IL-33/ST2信号通路对于EAE动物保护作用的机制研究

Multiple sclerosis (MS) is a chronic disease associated with inflammation and demyelination in the central nervous system (CNS) and is thought to be medicated by autoimmune process. IL-33 is a new member of the IL-1 family; it has been shown to induce the production of Th2 cytokine and participate many kinds of autoimmune diseases. Our previous study demonstrated that IL-33 mRNA and protein were highly expressed in tissues of the CNS; IL-33 is located in the nucleus; IL-33 treatment significantly ameliorated the clinical symptom of the disease. We speculate that IL-33 could bind ST2 which expressed in microglial cells and vascular endothelial cells to protect animal from EAE. The possible mechanism includes: negative regulation of TLR4 signal pathways; inhibit the NF-κB nuclear translocation; affect the interaction of microglial cells and autoreactive T cells, inhibition of release of inflammatory cytokines from microglial cells;reduction of the expression of P-selectin on the surface of vascular endothelial cells, blockade the recruitment of T cells to the CNS. Our project is promising to clarify the protective molecular mechanism of IL-33/ST2 signal pathway in the CNS and exploring the new strategies of prevention and treatment of MS.

多发性硬化症（MS）是一种慢性炎症性脱髓鞘性中枢神经系统自身免疫病。IL-33属IL-1家族新成员，可促进Th2型细胞因子产生，并参与多种自身免疫病发生。申报者前期发现：小鼠中枢神经系统高表达IL-33 mRNA和蛋白；IL-33表达在细胞核内；注射重组IL-33减轻小鼠实验性自身免疫性脑脊髓炎（EAE）的症状，对动物起保护作用。申报者推测，IL-33可通过与小胶质细胞和血管内皮细胞表面ST2结合而保护EAE，其机制可能为：负调节TLR4信号通路，抑制TLR4下游NF-κB的核转位；影响小胶质细胞和自身反应性T细胞相互作用，抑制小胶质细胞产生炎症因子；降低血管内皮细胞表面P-选择素（P-selectin）表达，阻止自身反应性T细胞进入中枢神经系统。本项目可望阐明中枢神经系统IL-33/ST2信号通路参与对EAE动物保护作用的分子机制，并为探寻防治MS的新策略提供实验依据。

多发性硬化症（multiple sclerosis，MS）是以神经脱髓鞘为主要病理改变的中枢神经系统（CNS）炎症性疾病。用于研究MS的经典动物模型是实验性自身免疫性脑脊髓炎（experimental autoimmune encephalomyelitis，EAE）。IL-33被最近认为是IL-1家族的新成员，IL-33主要介导Th2细胞应答，诱导Th2型细胞因子产生。本课题主要观察正常小鼠和EAE小鼠中枢神经系统内IL-33表达、来源及其参与EAE发病的作用及机制.IL-33 表达于正常小鼠中枢神经系统，确定了IL-33在中枢神经系统的细胞来源。抗IL-33多克隆抗体可增强Th1和Th17细胞应答，抗IL-33多抗明显降低脾脏、淋巴结CD11c+CD8α+DC数量，但不影响Treg数量。本课题为临床治疗多发性硬化症提供依据和靶点。