IL-1β介导脓毒症新生小鼠脑白质轴突低髓鞘化的分子机制

Periventricular white matter(PWM) damage (PWMD) induced by sepsis in perinatal period could result in cerebral palsy. Inflammation occurred in the PWM is the main reason of PWMD. Axonal hypomyelination in the PWM is the major pathological characteristic of PWMD. However, its mechanism remains obscure. Studies have shown that IL-1β is involved in axonal hypomyelination in the PWM. Oligodendrocyte precursors (OPCs) maturation through Fyn/MEK/ERK signaling pathway and axonal development by tau phosphorylation are essential for myelination. Our preliminary data have shown that IL-1β could inhibit OPCs maturation and axonal development. Therefore, we hypothesize that IL-1β could prevent OPCs maturation through inhibiting Fyn/MEK/ERK signaling pathway and axonal development by abnormal hyperphosphorylation of tau. These would lead to axonal hypomyelination in the PWMD induced by sepsis. This study attempts to elucidate the molecular mechanisms by which microglia-derived IL-1β might induce hypomyelination in the PWMD using DTI imaging and confocal microscopy, electronic microscopy, in situ hybridization etc. It is envisaged that IL-1β may serve as a potential therapeutic target for prevention of cerebral palsy induced by sepsis.

新生儿脓毒症引发的脑室周边白质(PWM)损伤(PWMD)可导致小儿脑瘫。PWM内炎症反应是脓毒症PWMD的重要原因。轴突低髓鞘化是脓毒症PWMD的主要病理特征，但其机制不明。研究表明白介素-1β(IL-1β)参与PWM轴突低髓鞘化。Fyn/MEK/ERK通路诱导少突胶质前体细胞(OPCs)分化成熟和tau蛋白磷酸化介导轴突正常发育是PWM轴突髓鞘化的必要条件。前期研究发现IL-1β可导致OPCs分化成熟障碍及轴突发育异常。由此，我们提出炎症反应释放的IL-1β通过抑制Fyn/MEK/ERK导致OPCs分化成熟障碍和激活p38-MAPkinase导致轴突tau蛋白异常过度磷酸化是脓毒症PWM轴突低髓鞘化的重要机制。本项目拟采用核磁共振弥散张量成像、激光共聚焦、电镜、原位杂交等方法，阐明IL-1β介导脓毒症PWM轴突低髓鞘化的分子机制，从而为防治脓毒症脑瘫提供新的靶点。

新生儿脓毒症引发的脑室周边白质(PWM)损伤(PWMD)可导致小儿脑瘫。PWM内炎症反应是脓毒症PWMD的重要原因。轴突低髓鞘化是脓毒症PWMD的主要病理特征，但其机制不明。我们的研究发现：脓毒症新生幼鼠脑室周边白质内发生神经炎症反应，激活小胶质细胞释放炎症介质白介素-1β(IL-1β)。炎症反应释放的IL-1β通过抑制Fyn/MEK/ERK导致OPCs分化成熟障碍和激活p38-MAPkinase导致轴突损伤是脓毒症PWM轴突低髓鞘化的重要机制。本项目拟采用核磁共振弥散张量成像、激光共聚焦、电镜、原位杂交等方法，阐明IL-1β介导脓毒症PWM轴突低髓鞘化的分子机制，从而为防治脓毒症脑瘫提供新的靶点。