Expression of the secondary granule proteins major basic protein 1 (MBP-1) and eosinophil peroxidase (EPX) is required for eosinophilopoiesis in mice
Expression of the secondary granule proteins major basic protein 1 (MBP-1) and eosinophil peroxidase (EPX) is required for eosinophilopoiesis in mice
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DOI：
10.1182/blood-2013-01-473405
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发表时间：
2013-08-01
期刊：
影响因子：
20.3
通讯作者：
Lee, Nancy A.
中科院分区：
文献类型：
--
作者：
Doyle, Alfred D.;Jacobsen, Elizabeth A.;Lee, Nancy A.
嗜酸性粒细胞活动通常与过敏性疾病，如哮喘和伴随寄生虫感染的病理有关。据推测，这些活性部分是由储存在这些粒细胞次级颗粒中的阳离子蛋白的释放介导的。储存在这些次级颗粒中的大部分蛋白质（按质量计算）是主要碱性蛋白1 （MBP-1）和嗜酸性过氧化物酶（EPX）。不可预见的是，针对编码这些蛋白的基因的敲除方法表明，与仅含有单一MBP-1或EPX缺陷的小鼠不同，缺乏这两种颗粒蛋白导致外周血嗜酸性粒细胞几乎完全丧失，而对任何其他造血谱系没有明显影响。此外，MBP-1和EPX的缺失促进了骨髓中嗜酸性细胞谱系的祖细胞的缺失，确定了嗜酸性细胞生成中的特定阻断是致病事件。值得注意的是，在骨髓祖细胞的体外培养中也观察到这种嗜酸性粒细胞的阻断，并且在体内不能通过过继骨髓移植恢复，这表明骨髓祖细胞存在细胞自主缺陷。这些观察结果暗示了颗粒蛋白基因表达作为嗜酸性粒细胞形成的调节因子的作用，并提供了另一种先天性嗜酸性粒细胞缺乏的小鼠品系。
Eosinophil activities are often linked with allergic diseases such as asthma and the pathologies accompanying helminth infection. These activities have been hypothesized to be mediated, in part, by the release of cationic proteins stored in the secondary granules of these granulocytes. The majority of the proteins stored in these secondary granules (by mass) are major basic protein 1 (MBP-1) and eosinophil peroxidase (EPX). Unpredictably, a knockout approach targeting the genes encoding these proteins demonstrated that, unlike in mice containing a single deficiency of only MBP-1 or EPX, the absence of both granule proteins resulted in the near complete loss of peripheral blood eosinophils with no apparent impact on any other hematopoietic lineage. Moreover, the absence of MBP-1 and EPX promoted a concomitant loss of eosinophil lineage-committed progenitors in the marrow, identifying a specific blockade in eosinophilopoiesis as the causative event. Significantly, this blockade of eosinophilopoiesis is also observed in ex vivo cultures of marrow progenitors and is not rescued in vivo by adoptive bone marrow engraftment, suggesting a cell-autonomous defect in marrow progenitors. These observations implicate a role for granule protein gene expression as a regulator of eosinophilopoiesis and provide another strain of mice congenitally deficient of eosinophils.