Activated microglia drive demyelination via CSF1R signaling.
Activated microglia drive demyelination via CSF1R signaling.
复制标题
活化的小胶质细胞通过CSF1R信号传导驱动脱髓鞘。
作者：
小胶质细胞增生是许多神经系统疾病的显著病理特征，包括多发性硬化症（MS），一种进行性自身免疫脱髓鞘疾病。小胶质细胞、实质中枢神经系统（CNS）巨噬细胞在脱髓鞘过程中的确切作用以及外周巨噬细胞的相对作用尚不完全清楚。用于鉴定小胶质细胞的经典标志物不能可靠地区分小胶质细胞和外周巨噬细胞，混淆分析。在这里，我们使用的遗传命运映射策略，以确定小胶质细胞的主要反应和脱髓鞘的铜（CUP）模型的关键效应。集落刺激因子1（CSF 1），也称为巨噬细胞集落刺激因子（M-CSF）-一种调节小胶质细胞发育和存活的分泌型细胞因子-在脱髓鞘白色病变中上调。用CSF 1 R抑制剂PLX 3397消耗小胶质细胞大大消除了CUP治疗引起的脱髓鞘、少突胶质细胞损失和反应性星形细胞增多。电子显微镜（EM）和连续阻滞面成像显示，髓鞘保持完整的CUP治疗小鼠的小胶质细胞耗尽。然而，这些CUP损伤的髓鞘丢失，并在小胶质细胞再增殖时被强烈吞噬。将CSF 1直接注射到CNS白色物质中诱导局灶性小胶质细胞增生和脱髓鞘，表明活性CSF 1信号传导可促进脱髓鞘。最后，在采用由小胶质细胞驱动的毒性星形胶质细胞表型方面有缺陷的小鼠在CUP治疗后仍然正常脱髓鞘，这暗示小胶质细胞而不是星形胶质细胞是CUP介导的脱髓鞘的主要驱动因素。总之，这些研究表明激活的小胶质细胞是脱髓鞘所必需的，并且可以直接驱动脱髓鞘，并在这些事件中涉及CSF 1信号传导。
Microgliosis is a prominent pathological feature in many neurological diseases including multiple sclerosis (MS), a progressive auto-immune demyelinating disorder. The precise role of microglia, parenchymal central nervous system (CNS) macrophages, during demyelination, and the relative contributions of peripheral macrophages are incompletely understood. Classical markers used to identify microglia do not reliably discriminate between microglia and peripheral macrophages, confounding analyses. Here, we use a genetic fate mapping strategy to identify microglia as predominant responders and key effectors of demyelination in the cuprizone (CUP) model. Colony-stimulating factor 1 (CSF1), also known as macrophage colony-stimulating factor (M-CSF) - a secreted cytokine that regulates microglia development and survival - is upregulated in demyelinated white matter lesions. Depletion of microglia with the CSF1R inhibitor PLX3397 greatly abrogates the demyelination, loss of oligodendrocytes, and reactive astrocytosis that results from CUP treatment. Electron microscopy (EM) and serial block face imaging show myelin sheaths remain intact in CUP treated mice depleted of microglia. However, these CUP-damaged myelin sheaths are lost and robustly phagocytosed upon-repopulation of microglia. Direct injection of CSF1 into CNS white matter induces focal microgliosis and demyelination indicating active CSF1 signaling can promote demyelination. Finally, mice defective in adopting a toxic astrocyte phenotype that is driven by microglia nevertheless demyelinate normally upon CUP treatment implicating microglia rather than astrocytes as the primary drivers of CUP-mediated demyelination. Together, these studies indicate activated microglia are required for and can drive demyelination directly and implicate CSF1 signaling in these events.