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首页> 外文期刊>Neuropathology: official journal of the Japanese Society of Neuropathology >Immunohistochemical characterization of microglia in Nasu-Hakola disease brains.
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Immunohistochemical characterization of microglia in Nasu-Hakola disease brains.

机译：Nasu-Hakola疾病大脑中小胶质细胞的免疫组织化学表征。

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Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder, characterized by progressive presenile dementia and formation of multifocal bone cysts, caused by genetic mutations of DNAX-activation protein 12 (DAP12) or triggering receptor expressed on myeloid cells 2 (TREM2). TREM2 and DAP12 constitute a receptor/adapter signaling complex expressed on osteoclasts, dendritic cells (DC), macrophages and microglia. Previous studies using knockout mice and mouse brain cell cultures suggest that a loss-of-function of DAP12/TREM2 in microglia plays a central role in the neuropathological manifestation of NHD. However, there exist no immunohistochemical studies that focus attention on microglia in NHD brains. To elucidate a role of microglia in the pathogenesis of NHD, we searched NHD-specific biomarkers and characterized their expression on microglia in NHD brains. Here, we identified allograft inflammatory factor 1 (AIF1, Iba1) and sialic acid binding Ig-like lectin 1 (SIGLEC1) as putative NHD-specific biomarkers by bioinformatics analysis of microarray data of NHD DC. We studied three NHD and eight control brains by immunohistochemistry with a panel of 16 antibodies, including those against Iba1 and SIGLEC1. We verified the absence of DAP12 expression in NHD brains and the expression of DAP12 immunoreactivity on ramified microglia in control brains. Unexpectedly, TREM2 was not expressed on microglia but expressed on a small subset of intravascular monocytes/macrophages in control and NHD brains. In the cortex of NHD brains, we identified accumulation of numerous Iba1-positive microglia to an extent similar to control brains, while SIGLEC1 was undetectable on microglia in all the brains examined. These observations indicate that human microglia in brain tissues do not express TREM2 and DAP12-deficient microglia are preserved in NHD brains, suggesting that the loss of DAP2/TREM2 function in microglia might not be primarily responsible for the neuropathological phenotype of NHD.
机译：Nasu-Hakola病（NHD）是一种罕见的常染色体隐性遗传疾病，其特征是进行性老年性痴呆和多灶性骨囊肿的形成，其原因是DNAX激活蛋白12（DAP12）的遗传突变或在髓样细胞2（TREM2）上表达的触发受体引起的。 TREM2和DAP12构成了在破骨细胞，树突状细胞（DC），巨噬细胞和小胶质细胞上表达的受体/衔接子信号复合物。先前使用基因敲除小鼠和小鼠脑细胞培养物的研究表明，小胶质细胞中DAP12 / TREM2的功能丧失在NHD的神经病理表现中起着核心作用。但是，尚无免疫组织化学研究将注意力集中在NHD大脑中的小胶质细胞上。为了阐明小胶质细胞在NHD发病机理中的作用，我们搜索了NHD特异性生物标志物，并表征了它们在NHD大脑中的小胶质细胞上的表达。在这里，我们通过对NHD DC的微阵列数据进行生物信息学分析，确定了同种异体移植炎症因子1（AIF1，Iba1）和唾液酸结合Ig样凝集素1（SIGLEC1）作为NHD特异性生物标志物。我们用16种抗体（包括针对Iba1和SIGLEC1的抗体）通过免疫组织化学研究了3个NHD和8个对照大脑。我们验证了在NHD大脑中DAP12表达的缺失以及在对照脑中分枝小胶质细胞上DAP12免疫反应性的表达。出乎意料的是，TREM2在小胶质细胞上不表达，但在对照和NHD脑中的一小部分血管内单核细胞/巨噬细胞中表达。在NHD大脑皮层中，我们确定了许多Iba1阳性小胶质细胞的积累，其程度与对照脑相似，而在所有检查的脑中小胶质细胞上均未检测到SIGLEC1。这些观察结果表明，脑组织中的人类小胶质细胞不表达TREM2，而在NHD大脑中保留了DAP12缺陷型小胶质细胞，这表明小胶质细胞中DAP2 / TREM2功能的丧失可能不是NHD的神经病理表型的主要原因。

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