Loss of the zona pellucida-binding protein 2 (Zpbp2) gene in mice impacts airway hypersensitivity and lung lipid metabolism in a sex-dependent fashion.

Cynthia Kanagaratham, Victoria Chiwara, Bianca Ho, Sanny Moussette, Mina Youssef, David Venuto, Lucie Jeannotte, Guillaume Bourque, Juan Bautista de Sanctis, Danuta Radzioch, Anna K Naumova
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引用次数: 7

Abstract

The human chromosomal region 17q12-q21 is one of the best replicated genome-wide association study loci for childhood asthma. The associated SNPs span a large genomic interval that includes several protein-coding genes. Here, we tested the hypothesis that the zona pellucida-binding protein 2 (ZPBP2) gene residing in this region contributes to asthma pathogenesis using a mouse model. We tested the lung phenotypes of knock-out (KO) mice that carry a deletion of the Zpbp2 gene. The deletion attenuated airway hypersensitivity (AHR) in female, but not male, mice in the absence of allergic sensitization. Analysis of the lipid profiles of their lungs showed that female, but not male, KO mice had significantly lower levels of sphingosine-1-phosphate (S1P), very long-chain ceramides (VLCCs), and higher levels of long-chain ceramides compared to wild-type controls. Furthermore, in females, lung resistance following methacholine challenge correlated with lung S1P levels (Pearson correlation coefficient 0.57) suggesting a link between reduced AHR in KO females, Zpbp2 deletion, and S1P level regulation. In livers, spleens and blood plasma, however, VLCC, S1P, and sphingosine levels were reduced in both KO females and males. We also find that the Zpbp2 deletion was associated with gain of methylation in the adjacent DNA regions. Thus, we demonstrate that the mouse ortholog of ZPBP2 has a role in controlling AHR in female mice. Our data also suggest that Zpbp2 may act through regulation of ceramide metabolism. These findings highlight the importance of phospholipid metabolism for sexual dimorphism in AHR.

小鼠透明带结合蛋白2 (Zpbp2)基因的缺失以性别依赖的方式影响气道过敏和肺脂质代谢。
人类染色体区域17q12-q21是儿童哮喘的最佳复制全基因组关联研究位点之一。相关的snp跨越一个大的基因组间隔,包括几个蛋白质编码基因。在这里,我们使用小鼠模型验证了位于该区域的透明带结合蛋白2 (ZPBP2)基因参与哮喘发病机制的假设。我们测试了携带Zpbp2基因缺失的敲除(KO)小鼠的肺表型。在没有过敏性致敏的情况下,这种缺失减轻了雌性小鼠的气道超敏反应(AHR),而不是雄性小鼠。肺脂质谱分析显示,与野生型对照相比,雌性KO小鼠的鞘氨醇-1-磷酸(S1P)、超长链神经酰胺(vlcc)水平显著降低,而雄性KO小鼠的长链神经酰胺水平显著升高。此外,在女性中,甲基胆碱刺激后的肺阻力与肺S1P水平相关(Pearson相关系数0.57),这表明KO女性AHR降低、Zpbp2缺失和S1P水平调节之间存在联系。然而,在肝脏、脾脏和血浆中,KO女性和男性的VLCC、S1P和鞘氨醇水平均降低。我们还发现Zpbp2缺失与邻近DNA区域甲基化的增加有关。因此,我们证明ZPBP2的小鼠同源物在控制雌性小鼠AHR中起作用。我们的数据也表明Zpbp2可能通过调节神经酰胺代谢而起作用。这些发现强调了磷脂代谢对AHR性别二态性的重要性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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