老年脑缺血时IL-4受体调节巨噬/小胶质细胞极化的作用及机制

项目名称： 老年脑缺血时IL-4受体调节巨噬/小胶质细胞极化的作用及机制

项目编号： No.81471177

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： 沈帆霞

作者单位： 上海交通大学

项目金额： 70万元

中文摘要： 神经炎性反应在缺血后脑损伤中起重要作用，巨噬/小胶质细胞是主要的炎性细胞，近来发现其激活后可产生经典激活型（M1）和替代激活型（M2），其中M1与炎性反应有关，而M2则具有神经保护作用。研究也发现上述极化受不同信号通路调控，IL-4/JAK/STAT6信号可促进M2的极化。我们的前期研究发现，与青年鼠相比老年鼠脑缺血后CD68+（M1标志）细胞、IL-1/IL-6等炎性因子增加，脑损伤也较为严重。已有报道老年鼠中IL-4R的表达缺陷，我们推测，老年鼠中IL-4/JAK/STAT6信号通路的缺陷抑制了M2的极化，从而导致M1细胞相应增多，其产生的炎性反应增加了脑组织的损伤。本项目将在老年鼠大脑中动脉栓塞模型中观察缺血后损伤局部M1、M2细胞的分布和数量，在此基础上，探讨老年鼠中IL-4/JAK/STAT6信号改变与巨噬/小胶质细胞M1极化和脑损伤间的关联，从而阐明老年脑缺血神经损伤的机制。

中文关键词： 缺血性脑血管病；IL-4/IL-4受体；小胶质细胞；巨噬细胞；极化

英文摘要： Neuroinflammation plays an important role in the ischemic brain injury, microglia/macrophage are the main inflammatoy cells in the ischemic brain. Microglia/macrophage can be activated into classical activated (M1) or alternatively activated （M2）cells. M2 macrophages are considered to initiate inflammatory responses, in contrast M2 is characterized by neuro-protection. More evidence indicated that microglia/macrophage polarization can be modulated through different signaling pathway, IL-4/JAK/STAT6 signaling skews macrophage function toward the M2 phenotype. Our pilot data show that IL-1β/IL-6 is highly up-regulated and much more CD68+ cells were found in peri-infarct region in aged ischemic mice brain than that of young mice. Our data also suggest that an increased inflammatory response to acute ischemic injury in the aged mice leads to more severe brain damage and functional deficits. More evidence indicated that IL-4 receptor expression is reduced in the aging brain. Since IL-4 induces macrophage polarization towards M2, we hypothesize that deficiency of IL-4/JAK/STAT6 signaling pathway inhibits activated microglia/macrophage shifting towards an M2 phenotype, therefore induces more M1 phenotype. We will use middle cerebral artery oclution model in aged mice to show that the dynamic of microglial/macrophage polarization in aged ischemic brain. IL-4/JAK/STAT6 will be assessed to see wehther they are involved in the microglia/ macrophage polarization in the aged ischemic brain. Finaly to investigete wehther serere brain injury in aged ischemia is associated with macrglial/macrophage polarization.

英文关键词： ischemic stroke;IL-4/IL-4 recptor;microglial;macrophage;polarization