Inflammation Immunobiology Section, Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, Maryland, USA.
Research Technologies Branch, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, USA.
J Leukoc Biol. 2019 Jan;105(1):151-161. doi: 10.1002/JLB.3AB0318-090RR. Epub 2018 Oct 4.
Eosinophil peroxidase (EPX) is a major constituent of the large cytoplasmic granules of both human and mouse eosinophilic leukocytes. Human EPX deficiency is a rare, autosomal-recessive disorder limited to the eosinophil lineage. Our intent was to explore the impact of EPX gene deletion on eosinophil content, structure, and function. In response to repetitive intranasal challenge with a filtrate of the allergen, Alternaria alternata, we found significantly fewer eosinophils peripherally and in the respiratory tracts of EPX mice compared to wild-type controls; furthermore, both the major population (Gr1 ) and the smaller population of Gr1 eosinophils from EPX mice displayed lower median fluorescence intensities (MFIs) for Siglec F. Quantitative evaluation of transmission electron micrographs of lung eosinophils confirmed the relative reduction in granule outer matrix volume in cells from the EPX mice, a finding analogous to that observed in human EPX deficiency. Despite the reduced size of the granule matrix, the cytokine content of eosinophils isolated from allergen-challenged EPX and wild-type mice were largely comparable to one another, although the EPX eosinophils contained reduced concentrations of IL-3. Other distinguishing features of lung eosinophils from allergen-challenged EPX mice included a reduced fraction of surface TLR4 cells and reduced MFI for NOD1. Interestingly, the EPX gene deletion had no impact on eosinophil-mediated clearance of gram-negative Haemophilus influenzae from the airways. As such, although no clinical findings have been associated with human EPX deficiency, our findings suggest that further evaluation for alterations in eosinophil structure and function may be warranted.
嗜酸性粒细胞过氧化物酶 (EPX) 是人类和小鼠嗜酸性粒细胞大细胞质颗粒的主要成分。人类 EPX 缺乏是一种罕见的常染色体隐性遗传病，仅局限于嗜酸性粒细胞谱系。我们的目的是探讨 EPX 基因缺失对嗜酸性粒细胞含量、结构和功能的影响。在反复鼻内用 Alternaria alternata 过敏原滤液进行攻击后，我们发现 EPX 小鼠外周血和呼吸道中的嗜酸性粒细胞明显减少，与野生型对照相比；此外，来自 EPX 小鼠的 Gr1 主要群体和 Gr1 嗜酸性粒细胞的较小群体的 Siglec F 中位荧光强度 (MFI) 均较低。对肺嗜酸性粒细胞透射电镜图像的定量评估证实，EPX 小鼠细胞中的颗粒外基质体积相对减少，这与人类 EPX 缺乏症观察到的结果类似。尽管颗粒基质的大小减小，但从过敏原攻击的 EPX 和野生型小鼠分离的嗜酸性粒细胞的细胞因子含量在很大程度上彼此相当，尽管 EPX 嗜酸性粒细胞中 IL-3 的浓度降低。来自过敏原攻击的 EPX 小鼠肺嗜酸性粒细胞的其他区别特征包括 TLR4 表面细胞的比例降低和 NOD1 的 MFI 降低。有趣的是，EPX 基因缺失对嗜酸性粒细胞清除气道中革兰氏阴性流感嗜血杆菌没有影响。因此，尽管尚未发现与人类 EPX 缺乏相关的临床发现，但我们的研究结果表明，可能需要进一步评估嗜酸性粒细胞结构和功能的改变。
