p62介导NLRP3炎症小体活化在脑白质轴突低髓鞘化中的作用:mtROS/琥珀酸机制

A cardiac arrest can result in a poor prognosis of the nervous system. Neuroinflammation plays an important role in brain injury. White matter hypomyelination is the main pathological feature of brain injury. At present, the mechanism of white matter hypomyelination induced by neuroinflammation has not been fully understood. Our previous studies have confirmed that release of IL-1β caused by microglial activation can lead to hypomyelination, suggesting that inhibiting the release of IL-1β by microglia is the key to improving the hypomyelination. Our preliminary experiments showed that the hypomyelination was improved with up-regulated p62 and down-regulated NLRP3/IL-1β in corpus callosum after intraperitoneal injection of H1 receptor antagonist in rats with cerebral ischemia and hypoxia. Accordingly, we hypothesized that autophagy was initiated and mtROS/succinic acid/NLRP3 inflammasomes/IL-1β pathway was blocked by up-regulated p62 in microglia, thereby improving hypomyelination in the model of hypoxic-ischemic brain injury. In this study, animal models, cell culture, electron microscopy and gene overexpression were used to elucidate up-regulated p62 blocking mtROS/succinic acid/NLRP3 inflammasomes/IL-1β pathway to improve hypomyelination in rats with hypoxic-ischemic brain injury, so as to provide new ideas for improving neurological prognosis in patients with cerebral resuscitation after cardiac arrest.

心脏骤停可导致神经系统预后不良。神经炎症是脑损伤的重要原因，白质轴突低髓鞘化是脑损伤的主要病理特征。目前神经炎症致缺血缺氧性脑白质轴突低髓鞘化的机制尚不明确，我们前期研究证实小胶质细胞释放的IL-1β可导致轴突低髓鞘化，提示抑制IL-1β释放是改善轴突低髓鞘化的关键。我们研究发现脑缺血缺氧大鼠腹腔注射H1受体拮抗剂后脑胼胝体内p62表达上调，NLRP3/IL-1β表达下调，轴突低髓鞘化得到改善，据此我们提出假说：小胶质细胞内p62上调后启动自噬并阻断mtROS/琥珀酸/NLRP3炎症小体/IL-1β通路进而改善缺血缺氧性脑白质轴突低髓鞘化。本项目拟采用动物模型、细胞培养、电镜、基因过表达等方法，从组织、细胞和分子层面阐明p62上调后阻断mtROS/琥珀酸/NLRP3炎症小体/IL-1β通路进而改善缺血缺氧后白质轴突低髓化的分子机制，从而为改善心脏骤停后脑复苏患者神经预后提供新思路。

心脏骤停可导致神经系统预后不良。神经炎症是脑损伤的重要原因，白质轴突低髓鞘化是脑损伤的主要病理特征。目前神经炎症致缺血缺氧性脑白质轴突低髓鞘化的机制尚不明确，我们前期研究证实小胶质细胞释放的IL-1β可导致轴突低髓鞘化，提示抑制IL-1β释放是改善轴突低髓鞘化的关键。我们研究发现脑缺血缺氧大鼠腹腔注射H1受体拮抗剂后脑胼胝体内p62表达上调，NLRP3/IL-1β表达下调，轴突低髓鞘化得到改善，本项目采用动物模型、细胞培养、电镜、基因过表达等方法，从组织、细胞和分子层面阐明p62上调后阻断mtROS/琥珀酸/NLRP3炎症小体/IL-1β通路进而改善缺血缺氧后白质轴突低髓化的分子机制，从而为改善心脏骤停后脑复苏患者神经预后提供新思路。