M2型小胶质细胞外泌体通过调控脑组织免疫炎症反应改善颅脑创伤认知功能预后的作用及机制研究

The immuno-inflammatory response in brain is an important pathological change after traumatic brain injury (TBI), which exerts an important influence on cognitive prognosis. However, the related pathological mechanism has not been elucidated. Microglia plays a significant role in immuno-inflammatory response in brain, and M2 microglia is anti-inflammatorily. In our previous research (total impact factor: 22.012), we found that the M2 microglia-derived exosomes (M2-Exo), which highly-express miR-21-5p that alleviates immuno-inflammatory response in blood-brain barrier and neuronal apoptosis after TBI, could reduce the expression of pro-inflammatory factors in injured brain, and improve the cognitive prognosis after TBI. Based on these findings, experiments on TBI mice and in vitro cultured cells (using the high-resolution hopping probe ion conductance microscopy) are designed to further investigate the function and mechanism of M2-Exo in TBI. The objectives of our proposed research include: 1. Prove the function of M2-Exo on improving the cognitive prognosis after TBI; 2. Clarify the function and mechanism of M2-Exo that inhibit excessive immuno-inflammatory response in brain in the acute and chronic phase of TBI; 3. Clarify the mechanism that M2-Exo improve the cognitive prognosis through regulating the immuno-inflammatory response, permeability of blood-brain barrier and neurodegeneration in brain after TBI. The outcome of this research will further explain the pathological mechanism that affect the cognitive prognosis after TBI. It will also provide insights into developing novel therapeutic strategies using exosomes and miRNA for TBI.

免疫炎症反应是颅脑创伤（TBI）后脑组织病程进展的重要环节，也是认知功能预后的关键影响因素，但其病理机制尚未阐明。小胶质细胞是脑组织免疫炎症反应的核心细胞，其M2型具有抑炎作用。课题组前期研究（累计IF>22）发现：M2型小胶质细胞外泌体（M2-Exo）高表达miR-21-5p（抗血脑屏障免疫炎症反应及神经元凋亡），并能抑制TBI后脑组织促炎因子的表达，改善认知功能预后。为深入研究M2-Exo的上述作用及机制，本课题拟借助TBI小鼠模型及离子电导显微镜等体外技术：1.明确M2-Exo改善TBI认知功能预后的作用；2.探明M2-Exo在TBI急、慢性期抑制脑组织过度免疫炎症反应的作用及机制；3.探明M2-Exo通过调控免疫炎症反应、血脑屏障通透性及神经退行性变，改善认知功能预后的机制。本研究将进一步阐明TBI认知功能预后的影响机制，为探索应用外泌体及miRNA治疗TBI的新策略提供理论依据。

免疫炎症反应是颅脑创伤（TBI）后脑组织病程进展的重要环节，也是认知功能预后的关键影响因素，但其病理机制尚未阐明。小胶质细胞是脑组织免疫炎症反应的核心细胞，其M2型具有抑炎作用。课题组前期研究发现：M2型小胶质细胞外泌体（M2-Exo）高表达miR-21-5p（抗血脑屏障免疫炎症反应及神经元凋亡），并能抑制TBI后脑组织促炎因子的表达，改善认知功能预后。为深入研究M2-Exo的上述作用及机制，本课题通过体内、体外实验，应用TBI小鼠模型及离子电导显微镜等体外技术，实现了以下目标：1.明确M2-Exo改善TBI认知功能预后的作用；2.探明M2-Exo在TBI急、慢性期抑制脑组织过度免疫炎症反应的作用及机制；3.探明M2-Exo通过调控免疫炎症反应、血脑屏障通透性及神经退行性变，改善认知功能预后的机制。研究成果进一步阐明TBI认知功能预后的影响机制，为探索应用外泌体及miRNA治疗TBI的新策略提供理论依据。