Th2-high/low哮喘气道上皮细胞差异表达microRNA在哮喘气道炎症中的作用和机制

Asthma can be classified into different molecular phenotypes such as Th2-high and -low asthma. Eosinophilic inflammation is more severe in Th2-high asthma as compared with Th2-low asthma. Airway epithelial cells play important roles in airway inflammation. We previously found that epithelial IL-25 expression is increased in Th2-high asthma when compared with Th2-low asthma, and is significantly correlated with airway eosinophilic inflammation in asthma. MicroRNAs (miRNAs) regulate gene expression at post-transcription level. We hypothesize that differentially expressed epithelial miRNAs between Th2-high and -low asthma play important roles in airway eosinophilic inflammation in asthma. Our preliminary data identified a set of differentially expressed miRNAs between Th2-high and Th2-low asthma, including miR-181b-5p. Epithelial miR-181b-5p levels were significantly correlated with airway eosinophilic inflammation. We aim to investigate the role of differentially expressed miRNA between Th2-high and -low asthma and their target genes in the pathogenesis of airway eosinophilic inflammation in asthma. This study will identify novel target for asthma therapy.

支气管哮喘可以分为Th2 high和Th2 low两种分子表型，Th2 high哮喘患者气道嗜酸性粒细胞炎症更加严重。气道上皮细胞异常表达的基因参与哮喘气道炎症，我们发现气道上皮细胞IL-25在Th2 high哮喘患者表达异常升高，且与气道嗜酸性粒细胞炎症的程度有显著相关性。microRNA（miRNA）对基因表达进行转录后调节，我们推测Th2 high和low哮喘之间气道上皮细胞差异表达的miRNA及其靶基因在气道嗜酸性粒细胞炎症中有重要作用。在前期工作中，通过对Th2 high和low哮喘患者气道刷片标本进行miRNA芯片检测，发现在Th2 high / low之间存在差异表达miRNA，其中miR-181b-5p的表达水平与气道嗜酸性粒细胞炎症程度有明显的相关性。我们拟研究Th2 high和low哮喘气道上皮细胞差异表达miRNA及其靶基因在气道炎症中的作用，为哮喘治疗提供新的靶点。

气道上皮细胞构成第一道物理屏障，而且参与哮喘气道粘液过度分泌和气道炎症等。MiRNA对基因表达进行转录后调节，在哮喘发病中有重要作用。本项目发现，type 2-low和type 2-high哮喘患者气道上皮细胞miRNA表达谱存在显著差异。通过对差异表达miRNA的深入研究，我们发现miR-218-5p通过下调CTNND2基因表达，发挥对哮喘气道炎症的保护作用。而miR-221-3p通过下调抗炎细胞因子CXCL17的表达，促进了哮喘气道炎症的发生。我们还发现ITLN在哮喘气道上皮细胞固有免疫细胞因子IL-25等的表达中有重要作用。以上研究成果说明，气道上皮细胞miRNA通过调节炎性细胞因子和固有免疫细胞因子表达，在哮喘气道炎症中发挥作用。这揭示了哮喘气道炎症发生的新机制。