The role of microRNA-155/liver X receptor pathway in experimental and idiopathic pulmonary fibrosis.
The role of microRNA-155/liver X receptor pathway in experimental and idiopathic pulmonary fibrosis.
复制标题
DOI：
10.1016/j.jaci.2016.09.021
复制
发表时间：
2017-06
期刊：
影响因子：
--
通讯作者：
McSharry C
中科院分区：
文献类型：
--
作者：
Kurowska-Stolarska M;Hasoo MK;Welsh DJ;Stewart L;McIntyre D;Morton BE;Johnstone S;Miller AM;Asquith DL;Millar NL;Millar AB;Feghali-Bostwick CA;Hirani N;Crick PJ;Wang Y;Griffiths WJ;McInnes IB;McSharry C
特发性肺纤维化（IPF）是进行性的，并且会迅速致命。需要提高对发病机制的了解才能促进新疗法的发展。表观遗传变化有助于 IPF；因此，microRNA可能揭示新的致病途径。我们试图确定 microRNA (miR)-155 在小鼠肺巨噬细胞和成纤维细胞、IPF 肺成纤维细胞的促纤维化功能中的调节作用，及其对实验性肺纤维化的贡献。通过组织学、胶原蛋白和促纤维化基因表达来分析博莱霉素诱导的野生型和 miR-155−/− 小鼠的肺纤维化。通过计算机和分子方法确定了机制，并在小鼠肺成纤维细胞和巨噬细胞以及 IPF 肺成纤维细胞中使用功能丧失和获得检测以及在体内使用特定抑制剂进行了验证。 miR-155−/− 小鼠出现肺纤维化加剧、胶原蛋白沉积增加、胶原蛋白 1 和 3 mRNA 表达、TGF-β 产生以及替代激活巨噬细胞的激活，这是由于肺成纤维细胞和巨噬细胞中 miR-155 靶基因肝 X 受体 (LXR)α 的失调所致。在实验性肺纤维化和 IPF 肺成纤维细胞中抑制 LXRα 可减轻加剧的纤维化反应。同样，miR-155 的强制表达降低了 IPF 和 miR-155−/− 成纤维细胞的促纤维化表型。我们在此描述了包含 miR-155 及其表观遗传 LXRα 靶点的分子途径，当解除调节时，该途径会导致致病性肺纤维化。调控 miR-155/LXR 通路可能具有治疗 IPF 的潜力。
Idiopathic pulmonary fibrosis (IPF) is progressive and rapidly fatal. Improved understanding of pathogenesis is required to prosper novel therapeutics. Epigenetic changes contribute to IPF; therefore, microRNAs may reveal novel pathogenic pathways. We sought to determine the regulatory role of microRNA (miR)-155 in the profibrotic function of murine lung macrophages and fibroblasts, IPF lung fibroblasts, and its contribution to experimental pulmonary fibrosis. Bleomycin-induced lung fibrosis in wild-type and miR-155−/− mice was analyzed by histology, collagen, and profibrotic gene expression. Mechanisms were identified by in silico and molecular approaches and validated in mouse lung fibroblasts and macrophages, and in IPF lung fibroblasts, using loss-and-gain of function assays, and in vivo using specific inhibitors. miR-155−/− mice developed exacerbated lung fibrosis, increased collagen deposition, collagen 1 and 3 mRNA expression, TGF-β production, and activation of alternatively activated macrophages, contributed by deregulation of the miR-155 target gene the liver X receptor (LXR)α in lung fibroblasts and macrophages. Inhibition of LXRα in experimental lung fibrosis and in IPF lung fibroblasts reduced the exacerbated fibrotic response. Similarly, enforced expression of miR-155 reduced the profibrotic phenotype of IPF and miR-155−/− fibroblasts. We describe herein a molecular pathway comprising miR-155 and its epigenetic LXRα target that when deregulated enables pathogenic pulmonary fibrosis. Manipulation of the miR-155/LXR pathway may have therapeutic potential for IPF.