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An endothelial microRNA-1-regulated network controls eosinophil trafficking in asthma and chronic rhinosinusitis.
Journal of Allergy and Clinical Immunology ( IF 11.4 ) Pub Date : 2020-02-01 , DOI: 10.1016/j.jaci.2019.10.031
Asawari Korde 1 , Farida Ahangari 1 , Maria Haslip 2 , Xuchen Zhang 3 , Qing Liu 1 , Lauren Cohn 1 , Jose L Gomez 1 , Geoffrey Chupp 1 , Jordan S Pober 4 , Anjelica Gonzalez 5 , Shervin S Takyar 1
Affiliation  

BACKGROUND Airway eosinophilia is a prominent feature of asthma and chronic rhinosinusitis (CRS), and the endothelium plays a key role in eosinophil trafficking. To date, microRNA-1 (miR-1) is the only microRNA known to be regulated in the lung endothelium in asthma models. OBJECTIVE We sought to determine the role of endothelial miR-1 in allergic airway inflammation. METHODS We measured microRNA and mRNA expression using quantitative RT-PCR. We used ovalbumin and house dust mite models of asthma. Endothelium-specific overexpression of miR-1 was achieved through lentiviral vector delivery or induction of a transgene. Tissue eosinophilia was quantified by using Congo red and anti-eosinophil peroxidase staining. We measured eosinophil binding with a Sykes-Moore adhesion chamber. Target recruitment to RNA-induced silencing complex was assessed by using anti-Argonaute2 RNA immunoprecipitation. Surface P-selectin levels were measured by using flow cytometry. RESULTS Serum miR-1 levels had inverse correlations with sputum eosinophilia, airway obstruction, and number of hospitalizations in asthmatic patients and sinonasal tissue eosinophilia in patients with CRS. IL-13 stimulation decreased miR-1 levels in human lung endothelium. Endothelium-specific overexpression of miR-1 reduced airway eosinophilia and asthma phenotypes in murine models and inhibited IL-13-induced eosinophil binding to endothelial cells. miR-1 recruited P-selectin, thymic stromal lymphopoietin, eotaxin-3, and thrombopoietin receptor to the RNA-induced silencing complex; downregulated these genes in the lung endothelium; and reduced surface P-selectin levels in IL-13-stimulated endothelial cells. In our asthma and CRS cohorts, miR-1 levels correlated inversely with its target genes. CONCLUSION Endothelial miR-1 regulates eosinophil trafficking in the setting of allergic airway inflammation. miR-1 has therapeutic potential in asthmatic patients and patients with CRS.

中文翻译:

内皮 microRNA-1 调节网络控制哮喘和慢性鼻窦炎中的嗜酸性粒细胞运输。

背景气道嗜酸性粒细胞增多是哮喘和慢性鼻窦炎(CRS)的突出特征,内皮在嗜酸性粒细胞运输中起关键作用。迄今为止,microRNA-1 (miR-1) 是已知的唯一一种在哮喘模型的肺内皮中受到调节的 microRNA。目的 我们试图确定内皮 miR-1 在过敏性气道炎症中的作用。方法 我们使用定量 RT-PCR 测量了 microRNA 和 mRNA 的表达。我们使用了哮喘的卵清蛋白和屋尘螨模型。miR-1 的内皮特异性过表达是通过慢病毒载体递送或转基因诱导实现的。通过使用刚果红和抗嗜酸性粒细胞过氧化物酶染色量化组织嗜酸性粒细胞增多。我们用 Sykes-Moore 粘附室测量了嗜酸性粒细胞的结合。通过使用抗 Argonaute2 RNA 免疫沉淀评估 RNA 诱导的沉默复合物的靶标募集。通过使用流式细胞术测量表面P-选择素水平。结果 血清 miR-1 水平与痰嗜酸性粒细胞增多、气道阻塞、哮喘患者的住院次数和 CRS 患者的鼻窦组织嗜酸性粒细胞增多呈负相关。IL-13 刺激降低了人肺内皮细胞中的 miR-1 水平。miR-1 的内皮特异性过表达减少了小鼠模型中的气道嗜酸性粒细胞增多和哮喘表型,并抑制了 IL-13 诱导的嗜酸性粒细胞与内皮细胞的结合。miR-1 将 P-选择素、胸腺基质淋巴细胞生成素、eotaxin-3 和血小板生成素受体募集到 RNA 诱导的沉默复合物;下调肺内皮中的这些基因;并降低 IL-13 刺激的内皮细胞中的表面 P-选择素水平。在我们的哮喘和 CRS 队列中,miR-1 水平与其靶基因呈负相关。结论 内皮 miR-1 调节过敏性气道炎症环境中的嗜酸性粒细胞运输。miR-1 在哮喘患者和 CRS 患者中具有治疗潜力。
更新日期:2020-02-06
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