Groh Janos, Basu Ranu, Stanley E Richard, Martini Rudolf
Department of Neurology, Developmental Neurobiology, University Hospital Wuerzburg, D-97080 Wuerzburg, Germany, and
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461.
J Neurosci. 2016 Feb 10;36(6):1890-901. doi: 10.1523/JNEUROSCI.3427-15.2016.
Previous studies in myelin-mutant mouse models of the inherited and incurable nerve disorder, Charcot-Marie-Tooth (CMT) neuropathy, have demonstrated that low-grade secondary inflammation implicating phagocytosing macrophages amplifies demyelination, Schwann cell dedifferentiation and perturbation of axons. The cytokine colony stimulating factor-1 (CSF-1) acts as an important regulator of these macrophage-related disease mechanisms, as genetic and pharmacologic approaches to block the CSF-1/CSF-1R signaling result in a significant alleviation of pathological alterations in mutant peripheral nerves. In mouse models of CMT1A and CMT1X, as well as in human biopsies, CSF-1 is predominantly expressed by endoneurial fibroblasts, which are closely associated with macrophages, suggesting local stimulatory mechanisms. Here we investigated the impact of cell-surface and secreted isoforms of CSF-1 on macrophage-related disease in connexin32-deficient (Cx32def) mice, a mouse model of CMT1X. Our present observations suggest that the secreted proteoglycan isoform (spCSF-1) is predominantly expressed by fibroblasts, whereas the membrane-spanning cell-surface isoform (csCSF-1) is expressed by macrophages. Using crossbreeding approaches to selectively restore or overexpress distinct isoforms in CSF-1-deficient (osteopetrotic) Cx32def mice, we demonstrate that both isoforms equally regulate macrophage numbers dose-dependently. However, spCSF-1 mediates macrophage activation and macrophage-related neural damage, whereas csCSF-1 inhibits macrophage activation and attenuates neuropathy. These results further corroborate the important role of secondary inflammation in mouse models of CMT1 and might identify specific targets for therapeutic approaches to modulate innate immune reactions.
Mouse models of Charcot-Marie-Tooth neuropathy have indicated that low-grade secondary inflammation involving phagocytosing macrophages amplifies demyelination, Schwann cell dedifferentiation, and perturbation of axons. The recruitment and pathogenic activation of detrimental macrophages is regulated by CSF-1, a cytokine that is mostly expressed by fibroblasts in the diseased nerve and exists in three isoforms. We show that the cell-surface and secreted isoforms of CSF-1 have opposing effects on macrophage activation and disease progression in a mouse model of CMT1X. These insights into opposing functions of disease-modulating cytokine isoforms might enable the development of specific therapeutic approaches.
先前针对遗传性且无法治愈的神经疾病——夏科-马里-图思（CMT）神经病的髓鞘突变小鼠模型开展的研究表明，涉及吞噬巨噬细胞的低度继发性炎症会加剧脱髓鞘、施万细胞去分化以及轴突紊乱。细胞因子集落刺激因子-1（CSF-1）作为这些与巨噬细胞相关疾病机制的重要调节因子，因为阻断CSF-1/CSF-1R信号传导的基因和药理学方法可显著减轻突变体周围神经的病理改变。在CMT1A和CMT1X小鼠模型以及人体活检中，CSF-1主要由与巨噬细胞密切相关的神经内膜成纤维细胞表达，提示存在局部刺激机制。在此，我们研究了CSF-1的细胞表面和分泌型异构体对CMT1X小鼠模型（连接蛋白32缺陷（Cx32def）小鼠）中与巨噬细胞相关疾病的影响。我们目前的观察结果表明，分泌型蛋白聚糖异构体（spCSF-1）主要由成纤维细胞表达，而跨膜细胞表面异构体（csCSF-1）由巨噬细胞表达。利用杂交方法在CSF-1缺陷（骨质石化）的Cx32def小鼠中选择性恢复或过表达不同的异构体，我们证明这两种异构体均以剂量依赖方式同等调节巨噬细胞数量。然而，spCSF-1介导巨噬细胞活化和与巨噬细胞相关的神经损伤，而csCSF-1抑制巨噬细胞活化并减轻神经病变。这些结果进一步证实了继发性炎症在CMT1小鼠模型中的重要作用，并可能为调节先天免疫反应的治疗方法确定特定靶点。
夏科-马里-图思神经病的小鼠模型表明，涉及吞噬巨噬细胞的低度继发性炎症会加剧脱髓鞘、施万细胞去分化以及轴突紊乱。有害巨噬细胞的募集和致病性活化受CSF-1调节，CSF-1是一种细胞因子，在患病神经中主要由成纤维细胞表达，并且以三种异构体形式存在。我们表明，在CMT1X小鼠模型中，CSF-1的细胞表面和分泌型异构体对巨噬细胞活化和疾病进展具有相反的作用。对疾病调节细胞因子异构体相反功能的这些见解可能有助于开发特定的治疗方法。
