脑卒中诱导的脑组织炎症与外周免疫抑制双向效应的免疫机制研究

项目名称： 脑卒中诱导的脑组织炎症与外周免疫抑制双向效应的免疫机制研究

项目编号： No.81471171

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 祝胜美

作者单位： 浙江大学

项目金额： 70万元

中文摘要： 脑卒中诱导脑组织炎症反应和外周免疫系统抑制（SIID）双向效应，目前治疗手段有限。T细胞和巨噬细胞（mФs）参与脑组织炎症和SIID的发生，机制未明。脑卒中后，高迁移率蛋白B1(HMGB1)由坏死神经元释放，我们前期研究发现，HMGB1作用于T细胞与mФs，介导脑损伤；HMGB1尚可释放入血，而大剂量HMGB1诱导T细胞免疫功能抑制。应用HMGB1抑制剂甘草甜素可改善脑卒中脑组织炎症及外周T细胞减少。因T细胞与mФs存在交互作用，故我们推测，脑卒中后释放的HMGB1可能通过调控T细胞功能，控制mФs分化介导中枢炎症或诱导SIID。我们拟应用多种转基因小鼠，采用流式细胞分选、细胞共培养等技术，观察中枢及外周T细胞及亚型、巨噬细胞各类亚型数量、功能改变，并观察HMGB1与它们的相关性，从而阐明T细胞与巨噬细胞在脑卒中双向效应中的作用及HMGB1的角色和机制，为脑卒中的防治提供新靶标及新思路。

中文关键词： 脑卒中；炎症；免疫抑制；高迁移率蛋白B1

英文摘要： Two differenc responses ocurred post cerebral ischemic injury, which includes central inflammation and peripheral stroke-induced immunodepression (SIID)，characterized by increased macrophage and T cells in injuryed brain tand lymphopenia in peripheral system, respectively. However, the mechanisms of both above responses remian unclear. Hign-mobility group box 1 protein (HMGB1), a novel cytokine-like protein, is released by necrotic neurons after storke. Our pilot results show that HMGB1 mediated inflammatory response by acting on T cells and macrophages (mФs). In addition, HMGB1 is released in the peripheral blood due to blood-brain barrier damage after stroke. Previous studies believed that high-dose of HMGB1 induced T cell immunosuppression. Our preliminary research show that Glycyrrhizin, a HMGB1 inhibitor ameliorated central inflammation and peripheral lymphopenia. The crosstalk of T cells and macrophages, as well as the terminal effectors of macropphages for brian injury are well-known. Therefore, we speculated that HMGB1 might regulate phenotye and function of macrophages through inducing T cell polarization, then mediate brain injury, and also, the high level of HMGB1 in the blood may contribute to SIID through regulating T cell-mediated immunity. In this study, we will investigate the numbers and functions of T cell, its subtypes and macrophage subtypes, as well as crosstalk of T cells and macrophages in the inchemic brain and peripheral organs, clarify the immunological mechanisms of HMGB1 iducing brian inflammation and inspect the relationship between HMGB1 realease and SIID by using flow cytometry, immunoflurecent staining and biomarker system in rodents' ischemic stroke model. Our study will offer new insight for basic and clinical research and provide new drug-target for treatment and precaution of stroke patients.

英文关键词： stroke;inflammation;immunodepression;HMGB1