Kurowska-Stolarska Mariola, Hasoo Manhl K, Welsh David J, Stewart Lynn, McIntyre Donna, Morton Brian E, Johnstone Steven, Miller Ashley M, Asquith Darren L, Millar Neal L, Millar Ann B, Feghali-Bostwick Carol A, Hirani Nikhil, Crick Peter J, Wang Yuqin, Griffiths William J, McInnes Iain B, McSharry Charles
Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
J Allergy Clin Immunol. 2017 Jun;139(6):1946-1956. doi: 10.1016/j.jaci.2016.09.021. Epub 2016 Oct 14.
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.
特发性肺纤维化（IPF）呈进行性发展且致死率高。为研发新的治疗方法，需要更深入地了解其发病机制。表观遗传变化与IPF相关；因此，微小RNA可能揭示新的致病途径。
我们试图确定微小RNA（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影响。
通过组织学、胶原蛋白和促纤维化基因表达分析野生型和miR-155小鼠中博来霉素诱导的肺纤维化。通过计算机模拟和分子方法确定机制，并在小鼠肺成纤维细胞和巨噬细胞、IPF肺成纤维细胞中使用功能缺失和功能获得试验进行验证，在体内使用特异性抑制剂进行验证。
miR-155小鼠出现了加重的肺纤维化、胶原沉积增加、胶原1和3 mRNA表达增加、转化生长因子-β产生增加以及替代性活化巨噬细胞的活化，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可减轻加重的纤维化反应。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。
我们在此描述了一条由miR-155及其表观遗传LXRα靶标组成的分子途径，该途径失调会导致致病性肺纤维化。操纵miR-155/LXR途径可能对IPF具有治疗潜力。
