期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 139, 期 6, 页码 1946-1956出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2016.09.021
关键词
MicroRNA-155; lung fibrosis; liver X receptor; fibroblasts; alternatively activated macrophages
资金
- Arthritis Research UK [19213]
- British Heart Foundation [FS/08/035/25309]
- Ministry of Higher Education and Scientific Research, Republic of Iraq
- Medical Research Scotland [657-2012]
- Lamellar Biomedical Ltd, Bellshill, United Kingdom
- National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases [P30 AR061271, K24 AR060297]
- British Pigeon Fanciers' Medical Research Trust
- Biotechnology & Biological Sciences Research Council [BB/I001735/1, BB/L001942/1]
- Biotechnology and Biological Sciences Research Council [BB/I001735/1] Funding Source: researchfish
- British Heart Foundation [FS/08/035/25309] Funding Source: researchfish
- British Lung Foundation [MRCPHD07-1] Funding Source: researchfish
- Chief Scientist Office [ETM/330, ETM/153] Funding Source: researchfish
- Medical Research Council [MR/K015206/1, G0901697] Funding Source: researchfish
- Versus Arthritis [19213] Funding Source: researchfish
- BBSRC [BB/I001735/1] Funding Source: UKRI
- MRC [MR/K015206/1, G0901697] Funding Source: UKRI
Background: 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. Objectives: 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. Methods: 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. Results: miR-155(-/-) mice developed exacerbated lung fibrosis, increased collagen deposition, collagen 1 and 3 mRNA expression, TGF-beta production, and activation of alternatively activated macrophages, contributed by deregulation of the miR-155 target gene the liver X receptor (LXR)alpha in lung fibroblasts and macrophages. Inhibition of LXR alpha 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. Conclusions: We describe herein a molecular pathway comprising miR-155 and its epigenetic LXRa target that when deregulated enables pathogenic pulmonary fibrosis. Manipulation of the miR-155/LXR pathway may have therapeutic potential for IPF.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据