Lung miRNA profiles show a time-of-day response in house dust mite-induced allergic asthma in mice.
Lung miRNA profiles show a time-of-day response in house dust mite-induced allergic asthma in mice.
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肺部 miRNA 谱显示了屋尘螨诱发的小鼠过敏性哮喘的随时间变化。
DOI：
10.1002/clt2.12057
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发表时间：
2021
影响因子：
4.4
通讯作者：
Srinivasan,Ashokkumar
中科院分区：
文献类型：
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作者：
Sundar,IsaacKirubakaran;Srinivasan,Ashokkumar
哮喘是一种慢性炎症性肺部疾病，对疾病的严重程度表现出时间效应（气道炎症增加和肺功能改变）。1最近的研究支持miRNAs在哮喘表型/内型的分子病理生理学中的功能性作用2，3通过转录后基因调节人气道、哮喘患者免疫细胞和过敏性哮喘小鼠模型中的关键信号通路和细胞过程。4-6然而，miRNAs表达的节律性变化是否是哮喘及其急性发作期间观察到的时间效应的原因尚不清楚。在这项研究中，我们利用NanoString的高通量miRNAs和mRNA分析，使用屋尘螨（HDM）诱导的过敏性哮喘模型确定时间效应。我们证明了HDM在Zeitgeber时间（ZT 0：6：00 a. m或ZT 12：6：00 pm）显示差异表达（DE）miRNA及其预测的mRNA，反映了哮喘表型。DE分析显示，与PBS（对照）相比，ZT 0与ZT 12 HDM暴露小鼠的miRNA表达存在强烈的时间差异。我们发现6种miRNA（下调：miR-125 B-5 p、miR-125 a-5 p、miR-150、miR-23 a、miR-23 B和miR-15 B b）和3种miRNA（上调：miR-652、miR-200 B和miR-200 c）在ZT 0时在HDM与PBS中显著（图1A、B），并且21种miRNA在ZT 12时在HDM与PBS中显著下调和17种miRNA显著上调（图1C、D）。提供了在ZT 0和ZT 12时HDM组与PBS组中DE miRNA的分层聚类分析，沿着比较，以及它们的倍数变化/比率、p值和假发现率（FDR）调整的p值（图1A-D）。当我们比较HDM与PBS组中的DE miRNA时，我们发现在ZT 0处的相同6种miRNA（下调）和3种miRNA（上调）在ZT 0和ZT 12处的常见miRNA DE中成对比较（图S1 A，B）。此外，在ZT 0和ZT 12时，HDM与PBS组的标准化计数的无监督聚类和主成分分析（PCA）显示了基于给药组分离的聚类（图S1 C-D）。在ZT 0和ZT 12，来自HDM相对于PBS组的标准化计数的层次聚类分析揭示了在ZT 12，PBS和HDM组中所有DE miRNA的紧密聚类，除了少数HDM ZT 0样品与PBS ZT 0或HDM ZT 12聚类（图S1 E）。
To the Editor, Asthma is a chronic inflammatory lung disease that shows a time‐of‐day effect (increased airway inflammation and altered lung function) on the severity of the disease. 1 Recent studies support the functional role of miRNAs in the molecular pathophysiology of asthma phenotypes/endotypes 2, 3 through the post‐transcriptional gene regulation of key signaling pathways and cellular processes in human airways, immune cells in asthmatics, and in mouse model of allergic asthma. 4–6 However, whether a rhythmic change in expression of miRNAs is responsible for the time‐of‐day effects observed during asthma and its exacerbations are not known.In this study, we utilized high‐throughput miRNA and mRNA profiling using NanoString to determine the time‐of‐day effects using the house dust mite (HDM)‐induced allergic asthma model. We demonstrate that timed dosing of HDM at Zeitgeber time (ZT0: 6: 00 a. m or ZT12: 6: 00 pm) shows differentially expressed (DE) miRNAs and their predicted mRNAs that are reflective of the asthma phenotype. DE analysis revealed a strong time‐of‐day difference in the miRNA expression at ZT0 versus ZT12 HDM exposed mice compared to PBS (control). We found 6 miRNAs (downregulated: miR‐125b‐5p, miR‐125a‐5p, miR‐150, miR‐23a, miR‐23b and miR‐15b) and 3 miRNAs (upregulated: miR‐652, miR‐200b and miR‐200c) significantly in HDM versus PBS at ZT0 (Figure 1A, B), and 21 miRNAs downregulated and 17 miRNAs upregulated significantly in HDM versus PBS at ZT12 (Figure 1C, D). Hierarchical cluster analysis of DE miRNAs in HDM versus PBS groups at ZT0 and ZT12 pairwise comparison along with their fold change/ratio, p‐value and the false discovery rate (FDR) adjusted p‐value is provided (Figure 1A–D). When we compared the DE miRNAs in HDM versus PBS group, we found the same 6 miRNAs (downregulated) and 3 miRNAs (upregulated) at ZT0 pairwise comparisons were among the common miRNAs DE at both ZT0 and ZT12 (Figure S1A, B). Additionally, unsupervised clustering and Principal Component Analysis (PCA) of normalized counts from HDM versus PBS groups at ZT0 and ZT12 showed clusters separated based on the treatment groups (Figure S1C–D). Hierarchical cluster analysis of normalized counts from HDM versus PBS groups at ZT0 and ZT12 revealed close clustering of all DE miRNAs in PBS and HDM groups at ZT12 except for few HDM ZT0 samples that were clustered with either the PBS ZT0 or HDM ZT12 (Figure S1E).