Department of Neurology, Section of Developmental Neurobiology, University of Würzburg, Josef-Schneiderstr. 11, 97080 Würzburg, Germany.
Brain. 2012 Jan;135(Pt 1):88-104. doi: 10.1093/brain/awr283. Epub 2011 Nov 16.
Previous studies in our laboratory have shown that in models for three distinct forms of the inherited and incurable nerve disorder, Charcot-Marie-Tooth neuropathy, low-grade inflammation implicating phagocytosing macrophages mediates demyelination and perturbation of axons. In the present study, we focus on colony-stimulating factor-1, a cytokine implicated in macrophage differentiation, activation and proliferation and fostering neural damage in a model for Charcot-Marie-Tooth neuropathy 1B. By crossbreeding a model for the X-linked form of Charcot-Marie-Tooth neuropathy with osteopetrotic mice, a spontaneous null mutant for colony-stimulating factor-1, we demonstrate a robust and persistent amelioration of demyelination and axon perturbation. Furthermore, functionally important domains of the peripheral nervous system, such as juxtaparanodes and presynaptic terminals, were preserved in the absence of colony-stimulating factor-1-dependent macrophage activation. As opposed to other Schwann cell-derived cytokines, colony-stimulating factor-1 is expressed by endoneurial fibroblasts, as revealed by in situ hybridization, immunocytochemistry and detection of β-galactosidase expression driven by the colony-stimulating factor-1 promoter. By both light and electron microscopic studies, we detected extended cell-cell contacts between the colony-stimulating factor-1-expressing fibroblasts and endoneurial macrophages as a putative prerequisite for the effective and constant activation of macrophages by fibroblasts in the chronically diseased nerve. Interestingly, in human biopsies from patients with Charcot-Marie-Tooth type 1, we also found frequent cell-cell contacts between macrophages and endoneurial fibroblasts and identified the latter as main source for colony-stimulating factor-1. Therefore, our study provides strong evidence for a similarly pathogenic role of colony-stimulating factor-1 in genetically mediated demyelination in mice and Charcot-Marie-Tooth type 1 disease in humans. Thus, colony-stimulating factor-1 or its cognate receptor are promising target molecules for treating the detrimental, low-grade inflammation of several inherited neuropathies in humans.
先前的研究表明，在三种不同形式的遗传性、不可治愈的神经疾病（如 Charcot-Marie-Tooth 神经病）的模型中，低水平的炎症涉及吞噬细胞，介导脱髓鞘和轴突的扰动。在本研究中，我们专注于集落刺激因子-1，这是一种与巨噬细胞分化、激活和增殖有关的细胞因子，并且在 Charcot-Marie-Tooth 神经病 1B 的模型中促进神经损伤。通过将 X 连锁形式的 Charcot-Marie-Tooth 神经病的模型与破骨细胞增多症小鼠（一种自发的集落刺激因子-1 缺失突变体）进行杂交，我们证明了脱髓鞘和轴突扰动的显著和持久改善。此外，在没有集落刺激因子-1 依赖性巨噬细胞激活的情况下，保留了周围神经系统的功能重要区域，如毗邻节和突触前末端。与其他许旺细胞衍生的细胞因子不同，集落刺激因子-1 由神经内膜成纤维细胞表达，如原位杂交、免疫细胞化学和由集落刺激因子-1 启动子驱动的β-半乳糖苷酶表达的检测所揭示。通过光镜和电子显微镜研究，我们在表达集落刺激因子-1 的成纤维细胞和神经内膜巨噬细胞之间检测到了扩展的细胞-细胞接触，这可能是成纤维细胞在慢性疾病神经中有效和持续激活巨噬细胞的前提。有趣的是，在 Charcot-Marie-Tooth 1 型患者的活检中，我们还发现了巨噬细胞和神经内膜成纤维细胞之间频繁的细胞-细胞接触，并鉴定后者为集落刺激因子-1 的主要来源。因此，我们的研究为集落刺激因子-1 在小鼠遗传性脱髓鞘和人类 Charcot-Marie-Tooth 1 型疾病中的类似致病性作用提供了有力证据。因此，集落刺激因子-1 或其同源受体是治疗几种遗传性神经病中有害的、低水平炎症的有前途的靶分子。
