IL-33在中枢神经系统内的主动释放及缓解自身反应性脑脊髓炎的作用及机制

自身反应性脑脊髓炎是神经系统最常见的自身免疫病，自发缓解机制不清楚。IL-33是IL-1家族的新成员，能否主动释放是未解之谜。神经中枢组成性高表达IL-33且水平与自身反应性脑脊髓炎存在明确的相关性，但具体作用及机制远未阐明。根据前期研究结果显示阻断IL-33的作用能显著加重疾病;疾病进程中，IL-33在中枢释放增多；申报者推测，神经中枢的星形胶质细胞和/或神经元在受到炎性刺激时能够主动释放IL-33，通过影响中枢粘附分子和趋化因子的表达，调控免疫细胞浸润；通过直接或间接作用，抑制浸润TH17、TH1细胞和CD8+T细胞的促炎作用，增强Treg细胞的抑制功能；最终减弱炎症，促进疾病缓解。本项目将使用受体ST2基因敲除鼠和IL-33基因敲除鼠，分别构建嵌合鼠，利用免疫学和神经学手段证明上述假说。阐明IL-33的主动释放方式，揭示自身反应性脑脊髓炎自发缓解的中枢机制，为临床诊疗提供新线索和靶点

The pathogenesis, especialy the mechanism of remission of autoimmune encephalomyelitis is not clear. IL-33, a new member of IL-1 family, is highly expressed in the central nervous system (CNS).Wether it can be actively secteted needs to be further addressed. The level of IL-33 is associated with autoimmune encephalomyelitis, however, what roles it plays is unknown. Based on the preliminary data, including blockade of IL-33 aggravates the encephalomyelitis and more IL-33 is released in the CNS, we propose that IL-33 which is actively released by pro-inflammatroy cytokine stimulated astrocytes and/or neurons can attenuate the inflammation and promote the remission of disease via influencing the expression of adhesion molecules and chemokines, regulating the infiltration of immune cells, inhibiting effector T cells function, and up regulating Tregs function in CNS. In the project, we will demonstrate the above hypothesis using IL-33 receptor ST2-/- mice and IL-33-/- mice and immunological methods. Our study will address the active release of IL-33 and the new mechanism of encephalomyelitis remission, as well as supply the new clues and targets for the clinical therapy.