Oligodendrocyte-microglia communication in the initiation of chronic secondary neuroinflammation

遗传导致的中枢神经系统疾病通常会导致慢性残疾，生活质量大幅下降，而且往往无法或难以治疗。其中许多伴有不确定致病相关性的神经性炎症。使用一种允许控制插入先前在人类多发性硬化症(MS)患者中描述的两个(蛋白脂蛋白)PLP1基因突变的策略，我们已经建立了反映慢性进行性多发性硬化症(PMS)以及遗传性痉挛截瘫(HSP)的几个重要方面的小鼠模型，包括髓鞘异常、轴突扰动、神经元丢失和中度神经炎症。基因失活实验支持这样的假设，即初级少突胶质细胞的扰动可以触发与病理相关的继发性神经炎症，从而驱动神经退化，基因失活实验明确地证明了在这些模型中，适应性免疫细胞的低级别炎症具有实质性的疾病改善作用。本提案旨在通过与PLP1相关的脑白质营养不良和遗传无关的神经退行性溶酶体储存性疾病的模型比较，确定在这些新生的小鼠中启动和促进这种有害的次级免疫反应的突变型少突胶质细胞和唾液粘附素阳性(SN+)激活的小胶质细胞的分子信号和细胞相互作用。在这些模型中识别常见和不同的炎症相关疾病途径将为我们提供病理机制方面的见解，并为治疗经前综合征和一些伴随病理性神经炎的遗传性神经系统疾病提供可能的治疗靶点。

Genetically caused neurological disorders of the CNS usually lead to chronic disability, substantial decline in quality of life and are often not or poorly treatable. Many of them are accompanied by neuroinflammation of uncertain pathogenic relevance. Using a strategy allowing controlled insertion of two (proteolipid protein) PLP1 gene mutations previously described in human multiple sclerosis (MS) patients, we have generated mouse models reflecting several important aspects of chronic progressive multiple sclerosis (PMS) but also hereditary spastic paraplegia (HSP) including myelin abnormalities, axonal perturbation, neuron loss and moderate neuroinflammation. In favour of the hypothesis that primary oligodendroglial perturbation can trigger pathologically-relevant secondary neuroinflammation that drives neurodegeneration, genetic inactivation experiments unequivocally demonstrated a substantial disease-modifying impact of low-grade inflammation by adaptive immune cells in these models. The present proposal is aimed to identify molecular signals and cellular interactions of mutant oligodendrocytes and sialoadhesin-positive (Sn+) activated microglia that initiate and promote this detrimental secondary immune reaction in these newly generated mice in comparison with models for a PLP1-related leukodystrophy and a genetically unrelated neurodegenerative lysosomal storage disease also associated with early axonal damage and neuroinflammation. Identifying common and distinct inflammation-related disease pathways in these models will provide us with pathomechanistic insights as well as putative therapeutic targets for treatment of PMS and some genetically-mediated disorders of the nervous system accompanied by pathogenic neuroinflammation.