Pulmonary microRNA profiles identify involvement of Creb1 and Sec14l3 in bronchial epithelial changes in allergic asthma.
Pulmonary microRNA profiles identify involvement of Creb1 and Sec14l3 in bronchial epithelial changes in allergic asthma.
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DOI：
10.1038/srep46026
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发表时间：
2017-04-06
影响因子：
4.6
通讯作者：
Krauss-Etschmann S
中科院分区：
文献类型：
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作者：
Bartel S;Schulz N;Alessandrini F;Schamberger AC;Pagel P;Theis FJ;Milger K;Noessner E;Stick SM;Kicic A;Eickelberg O;Freishtat RJ;Krauss-Etschmann S
哮喘是非常普遍的，但目前的治疗不能影响疾病的慢性过程。因此，了解潜在的早期分子事件非常重要。在这项研究中，我们的目的是使用microRNAs（miRNAs）-这是信号级联的关键调节因子-来识别迄今为止尚未表征的哮喘发病机制途径。因此，在来自卵清蛋白（OVA）诱导的过敏性气道炎症（AAI）小鼠的整个肺中评估了miRNA的失调。在计算机模拟预测的靶基因在报告基因测定中以及在室内尘螨（HDM）诱导的AAI和在空气-液体界面处培养的原代人支气管上皮细胞（NHBE）中得到证实。我们鉴定并验证了转录因子cAMP反应元件结合蛋白（Creb 1）及其转录共激活因子（Crtc 1 -3）作为miR-17、miR-144和miR-21的靶点。Sec 14-like 3（Sec 14 l3）-Creb 1的假定靶点-在两种哮喘模型和NHBE细胞中在IL 13处理后下调，而其表达与纤毛细胞发育相关，并且沿着杯状细胞化生的增加而降低。最后，我们建议，Creb 1/Crtc 1 -3和Sec 14 l3可能是重要的支气管上皮细胞对Th 2刺激的早期反应。这项研究表明，miRNA谱可用于识别在基于mRNA的策略中被忽视的新靶点。
Asthma is highly prevalent, but current therapies cannot influence the chronic course of the disease. It is thus important to understand underlying early molecular events. In this study, we aimed to use microRNAs (miRNAs) - which are critical regulators of signaling cascades - to identify so far uncharacterized asthma pathogenesis pathways. Therefore, deregulation of miRNAs was assessed in whole lungs from mice with ovalbumin (OVA)-induced allergic airway inflammation (AAI). In silico predicted target genes were confirmed in reporter assays and in house-dust-mite (HDM) induced AAI and primary human bronchial epithelial cells (NHBE) cultured at the air-liquid interface. We identified and validated the transcription factor cAMP-responsive element binding protein (Creb1) and its transcriptional co-activators (Crtc1-3) as targets of miR-17, miR-144, and miR-21. Sec14-like 3 (Sec14l3) - a putative target of Creb1 - was down-regulated in both asthma models and in NHBE cells upon IL13 treatment, while it’s expression correlated with ciliated cell development and decreased along with increasing goblet cell metaplasia. Finally, we propose that Creb1/Crtc1-3 and Sec14l3 could be important for early responses of the bronchial epithelium to Th2-stimuli. This study shows that miRNA profiles can be used to identify novel targets that would be overlooked in mRNA based strategies.