MicroRNA-155 is essential for TH2-mediated allergen-induced eosinophilic inflammation in the lung
MicroRNA-155 is essential for TH2-mediated allergen-induced eosinophilic inflammation in the lung
复制标题
DOI：
10.1016/j.jaci.2013.11.008
复制
发表时间：
2014-05-01
影响因子：
14.2
通讯作者：
Radinger, Madeleine
中科院分区：
文献类型：
--
作者：
Malmhall, Carina;Alawieh, Sahar;Radinger, Madeleine
背景资料：过敏性哮喘是一种慢性气道疾病，其特征是吸入过敏原后出现TH 2炎症和组织重塑。虽然TH 2概况是无可争议的，但导致这种异常TH 2概况的潜在分子机制仍不清楚。microRNAs（miRNAs）是一种短的非编码RNA，是免疫系统中基因表达的重要调节因子。然而，miRNAs，特别是miR-155在过敏性气道炎症调节中的作用尚未研究。目的：我们试图评估miR-155在小鼠过敏性气道炎症模型中的作用。研究方法：为了研究miR-155在体内调节过敏性炎症中的作用，我们使用了miR-155敲除（KO）和野生型（WT）小鼠致敏并暴露于卵清蛋白。结果如下：与WT对照动物相比，miR-155缺乏导致过敏原致敏和过敏原激发小鼠肺中嗜酸性粒细胞炎症和粘液分泌过多减少。这得到了miR-155 KO小鼠中TH 2细胞数量和气道TH 2细胞因子水平降低以及过敏原诱导的气道嗜酸性粒细胞趋化因子-2/CCL24和periostin水平完全消除的支持。在变应原激发前鼻内滴注eotaxin-2/CCL 24可部分恢复miR-155 KO小鼠的气道嗜酸性粒细胞增多，过继转移CD 4（+）T细胞可导致miR-155 KO和WT小鼠气道嗜酸性粒细胞增多程度相似。此外，与WT小鼠相比，在过敏原激发的miR-155 KO小鼠的气道中，转录因子PU.1（TH 2细胞因子产生的负调节因子）上调。结论：我们的数据提供了证据，证明miR-155通过转录因子PU.1调节TH 2反应，从而有助于调节过敏性气道炎症。
Background: Allergic asthma is a chronic disease of the conducting airways characterized by TH2 inflammation and tissue remodeling after exposure to inhaled allergens. Although the TH2 profile is undisputed, the underlying molecular mechanisms leading to this abnormal TH2 profile remain largely unclear. MicroRNAs (miRNAs) are short noncoding RNAs that are important regulators of gene expression in the immune system. However, the role of miRNAs, specifically miR-155, in the regulation of allergic airway inflammation is unexplored. Objectives: We sought to assess the contribution of miR-155 in a mouse model of allergic airway inflammation. Methods: To investigate a role for miR-155 in the regulation of allergic inflammation in vivo, we used miR-155 knockout (KO) and wild-type (WT) mice sensitized and exposed to ovalbumin. Results: miR-155 deficiency resulted in diminished eosinophilic inflammation and mucus hypersecretion in the lungs of allergen-sensitized and allergen-challenged mice compared with WT control animals. This was supported by a reduction in TH2 cell numbers and airway TH2 cytokine levels and complete abrogation of allergen-induced airway eotaxin-2/CCL24 and periostin levels in miR-155 KO mice. Intranasal instillation of eotaxin-2/CCL24 before allergen challenge partially restored airway eosinophilia in miR-155 KO mice, and adoptive transfer of CD4(+) T cells resulted in a similar degree of airway eosinophilia in miR-155 KO and WT mice. Furthermore, the transcription factor PU.1, a negative regulator of TH2 cytokine production, was upregulated in the airways of allergen challenged miR-155 KO mice compared with WT mice. Conclusions: Our data provides evidence that miR-155 contributes to the regulation of allergic airway inflammation by modulating TH2 responses through the transcription factor PU.1.