Children exposed to common aeroallergens may develop asthma that progresses into adulthood. Inflammation regulated by T helper 2 (Th2) cells, a specific subpopulation of CD4+ T lymphocytes, is involved in asthmatic injury. Herein, our microarray data indicated that microRNA-451a-5p (miRNA-451a) expression decreased by 4.6-fold and ETS proto-oncogene 1 (ETS1) increased by 2.2-fold in the peripheral blood lymphocytes isolated from asthmatic children (n = 4) as compared to control individuals (n = 4). The negative correlation between miRNA-451a and ETS1 was further validated in 40 CD4+ T cell samples (10 healthy vs. 30 asthmatic samples). In vitro, naïve CD4+ T cells isolated from control individuals were cultured under Th2 cell polarizing condition. miRNA-451a expression decreased while ETS1 increased in CD4+ T cells in the setting of Th2 cell polarization. Moreover, miRNA-451a knockdown enhanced Th2 cell polarization – cells positive for both GATA3 (GATA binding protein 3, a Th2-transcription factor) and CD4 increased, and the generation of Th2 cell cytokines, interleukin (IL)5 and IL13, increased. In contrast, miRNA-451a overexpression inhibited Th2 cell differentiation. Interestingly, dual-Luciferase assay proved ETS1 as a novel target of miRNA-451a. Moreover, enforced expression of ETS1 partially restored miRNA-451a-induced inhibition of IL5 and IL13, and increased the GATA3+CD4+ cell population. Collectively, our work demonstrates that downregulation of miRNA-451a upregulates ETS1 expression in CD4+ T cells, which may contribute to Th2 cell differentiation in pediatric asthma.
J Innate Immun

中文翻译：

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miRNA-451a 下调通过上调儿童哮喘中的 ETS1 促进 CD4+ T 细胞向 Th2 细胞分化

暴露于常见空气过敏原的儿童可能会患上哮喘，直至成年。由 T 辅助 2 (Th2) 细胞（CD4+ T 淋巴细胞的特定亚群）调节的炎症与哮喘损伤有关。在此，我们的微阵列数据表明，在从哮喘儿童中分离的外周血淋巴细胞中，microRNA-451a-5p（miRNA-451a）表达降低了 4.6 倍，ETS 原癌基因 1（ETS1）增加了 2.2 倍（n = 4 ) 与对照个体 ( n= 4）。miRNA-451a 和 ETS1 之间的负相关性在 40 个 CD4+ T 细胞样本（10 个健康样本与 30 个哮喘样本）中得到进一步验证。在体外，从对照个体分离的幼稚 CD4+ T 细胞在 Th2 细胞极化条件下培养。在 Th2 细胞极化的情况下，CD4+ T 细胞中 miRNA-451a 表达降低而 ETS1 增加。此外，miRNA-451a 敲低增强了 Th2 细胞极化——对 GATA3（GATA 结合蛋白 3，一种 Th2 转录因子）和 CD4 阳性的细胞增加，并且 Th2 细胞因子、白细胞介素 (IL)5 和 IL13 的产生增加。相反，miRNA-451a 过表达抑制 Th2 细胞分化。有趣的是，双荧光素酶检测证明 ETS1 是 miRNA-451a 的新靶点。而且，ETS1 的强制表达部分恢复了 miRNA-451a 诱导的 IL5 和 IL13 抑制，并增加了 GATA3+CD4+ 细胞群。总的来说，我们的工作表明，miRNA-451a 的下调会上调 CD4+ T 细胞中 ETS1 的表达，这可能有助于儿童哮喘中的 Th2 细胞分化。
J先天免疫