论文部分内容阅读
中枢神经系统疾病或损伤后,小胶质细胞介导的慢性神经炎症反应会损伤局部脑组织,加重病情,不利于神经功能的恢复。小胶质细胞的激活通过集落刺激因子1受体(CSF1R)信号通路,CSF1R抑制剂可阻断小胶质细胞的激活。抑制慢性神经炎症反应是治疗中枢神经系统疾病的有效方法,但长时间抑制小胶质细胞在临床实践中无法实现。值得注意的是,去掉CSF1R抑制剂可刺激中枢神经系统内新的小胶质细胞的彻底重激活。本课题组建立小鼠广泛性神经元丢失模型,在该模型中探讨急性小胶质细胞的消除及再激活的作用。神经元的丢失导致了较长时间的神经炎性反应,表现为小胶质细胞肿胀,并表达CD68和CD45;同时,细胞因子、趋化因子、补体及其他炎症信号的表达增加。小胶质细胞的再激活可以缓解上述炎症反应,还可以促进小鼠神经功能的恢复,即使该小鼠的海马神经元丢失80%,其在水迷宫测试中的得分与正常小鼠的得分相差无几。对突触的分析结果显示,小胶质细胞的再激活可增加PSD95和突触泡蛋白点状突触体的表达,提示小胶质细胞有助于重塑和调节突触的形态和功能。综上所述,本研究结果显示,小胶质细胞的短时间消除及再激活可能是一种新颖有效的方法用于减少神经炎性反应并促进脑功能恢复。
After the central nervous system diseases or injuries, microglial-mediated chronic neuroinflammation can damage the local brain tissue and aggravate the condition, which is not conducive to the recovery of nerve function. Microglia activation through the colony stimulating factor 1 receptor (CSF1R) signaling pathway, CSF1R inhibitors can block microglial activation. Inhibition of chronic neuroinflammation is an effective method for the treatment of central nervous system diseases. However, the inhibition of microglial cells for a long time can not be achieved in clinical practice. It is noteworthy that the removal of CSF1R inhibitors stimulates the complete reactivation of new microglia within the central nervous system. Our group established a model of extensive neuronal loss in mice and explored the role of elimination and reactivation of acute microglial cells in this model. The loss of neurons leads to neuroinflammatory reactions over a long period of time, manifested as swelling of microglial cells and expression of CD68 and CD45; meanwhile, expression of cytokines, chemokines, complement and other inflammatory signals is increased. Reactivation of microglia can alleviate the inflammatory reaction as described above, and can also promote the recovery of neurological function in mice. Even if the mouse hippocampal neuron lost 80%, its score in the water maze test is different from that in normal mice Not much. Analysis of the synapses revealed that reactivation of microglia increased the expression of PSD95 and synaptophysin punctiform synaptosomes, suggesting that microglia help remodel and regulate synaptic morphology and function. Taken together, the results of this study suggest that short-term microdissection and reactivation may be a novel and effective method for reducing neuroinflammatory responses and promoting brain function recovery.