Microglia are resident macrophages of the central nervous system, and their unique molecular signature is dependent upon CSF-1 signaling. Previous studies have demonstrated the importance of CSF-1R in survival and development of microglia in animal models, but the findings are of uncertain relevance to understanding the influence of CSF-1R on microglia in humans. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) [also known as adult onset leukoencephalopathy with spheroids and pigmented glia (ALSP)] is a neurodegenerative disorder primarily affecting cerebral white matter, most often caused by mutations of CSF1R. Therefore, we hypothesized that the molecular profile of microglia may be affected in HDLS. Semi-quantitative immunohistochemistry and quantitative transcriptomic profiling revealed reduced expression of IBA-1 and P2RY12 in both white and gray matter microglia of HDLS. In contrast, there was increased expression of CD68 and CD163 in microglia in affected white matter. In addition, expression of selective and specific microglial markers, including P2RY12, CX3CR1 and CSF-1R, were reduced in affected white matter. These results suggest that microglia in white matter in HDLS lose their homeostatic phenotype. Supported by gene ontology analysis, it is likely that an inflammatory phenotype is a key pathogenic feature of microglia in vulnerable brain regions of HDLS. Our findings suggest a potential mechanism of disease pathogenesis by linking aberrant CSF-1 signaling to altered microglial phenotype. They also support the idea that HDLS may be a primary microgliopathy. We observed increased expression of CSF-2 in gray matter compared to affected white matter, which may contribute to selective vulnerability of white matter in HDLS. Our findings suggest that methods that restore the homeostatic phenotype of microglia might be considered treatment approaches in HDLS.

中文翻译：

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CSF1R 相关白质脑病中稳态小胶质细胞表型的丧失。


小胶质细胞是中枢神经系统的常驻巨噬细胞，其独特的分子特征依赖于 CSF-1 信号传导。先前的研究已经证明了 CSF-1R 在动物模型中小胶质细胞生存和发育中的重要性，但这些发现对于理解 CSF-1R 对人类小胶质细胞的影响具有不确定的相关性。遗传性弥漫性球状体白质脑病 (HDLS) [也称为成人起病性球状体和色素性胶质细胞白质脑病 (ALSP)] 是一种主要影响脑白质的神经退行性疾病，最常由 CSF1R 突变引起。因此，我们假设 HDLS 中小胶质细胞的分子特征可能受到影响。半定量免疫组织化学和定量转录组分析显示，HDLS 的白质和灰质小胶质细胞中 IBA-1 和 P2RY12 的表达均减少。相反，受影响白质的小胶质细胞中 CD68 和 CD163 的表达增加。此外，受影响的白质中选择性和特异性小胶质细胞标记物（包括 P2RY12、CX3CR1 和 CSF-1R）的表达减少。这些结果表明 HDLS 中白质中的小胶质细胞失去了稳态表型。在基因本体分析的支持下，炎症表型很可能是 HDLS 脆弱脑区小胶质细胞的关键致病特征。我们的研究结果通过将异常的 CSF-1 信号传导与改变的小胶质细胞表型联系起来，提出了疾病发病机制的潜在机制。他们还支持 HDLS 可能是原发性小胶质细胞病的观点。我们观察到与受影响的白质相比，灰质中 CSF-2 的表达增加，这可能导致 HDLS 中白质的选择性脆弱性。 我们的研究结果表明，恢复小胶质细胞稳态表型的方法可能被视为 HDLS 的治疗方法。