FOXF1 Inhibits Pulmonary Fibrosis by Preventing CDH2-CDH11 Cadherin Switch in Myofibroblasts.
FOXF1 Inhibits Pulmonary Fibrosis by Preventing CDH2-CDH11 Cadherin Switch in Myofibroblasts.
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DOI：
10.1016/j.celrep.2018.03.067
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发表时间：
2018-04-10
期刊：
影响因子：
8.8
通讯作者：
Kalin TV
中科院分区：
文献类型：
--
作者：
Black M;Milewski D;Le T;Ren X;Xu Y;Kalinichenko VV;Kalin TV
特发性肺纤维化（IPF）的特征是分泌胶原的肌成纤维细胞异常积聚。由于对调节肌成纤维细胞扩增的分子机制的不完全理解，有效疗法的开发受到限制。FOXF 1转录因子在肺成纤维细胞中表达，但由于缺乏遗传小鼠模型，其在肺纤维化中的作用仍然未知。通过对人类IPF基因组学数据、肺活检和FOXF 1成纤维细胞特异性失活的转基因小鼠的综合分析，我们发现FOXF 1抑制肺纤维化。FOXF 1缺失增加肌成纤维细胞侵袭和胶原分泌，并促进从N-钙粘蛋白（CDH 2）到钙粘蛋白-11（CDH 11）的转换，这是获得促纤维化表型的关键步骤。FOXF 1直接与Cdh 2和Cdh 11启动子结合，并差异调节这些基因的转录。FOXF 1缺陷细胞中CDH 2的再表达或CDH 11的抑制降低了体外肌成纤维细胞侵袭。FOXF 1通过调节肺肌成纤维细胞中CDH 2向CDH 11的转换来抑制肺纤维化。Black等人证明FOXF 1通过阻止肌成纤维细胞中的CDH 2到CDH 11钙粘蛋白转换来抑制肺纤维化。
Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant accumulation of collagen-secreting myofibroblasts. Development of effective therapies is limited due to incomplete understanding of molecular mechanisms regulating myofibroblast expansion. FOXF1 transcription factor is expressed in resident lung fibroblasts, but its role in lung fibrosis remains unknown due to the lack of genetic mouse models. Through comprehensive analysis of human IPF genomics data, lung biopsies, and transgenic mice with fibroblast-specific inactivation of FOXF1, we show that FOXF1 inhibits pulmonary fibrosis. FOXF1 deletion increases myofibroblast invasion and collagen secretion and promotes a switch from N-cadherin (CDH2) to Cadherin-11 (CDH11), which is a critical step in the acquisition of the profibrotic phenotype. FOXF1 directly binds to Cdh2 and Cdh11 promoters and differentially regulates transcription of these genes. Re-expression of CDH2 or inhibition of CDH11 in FOXF1-deficient cells reduces myofibroblast invasion in vitro. FOXF1 inhibits pulmonary fibrosis by regulating a switch from CDH2 to CDH11 in lung myofibroblasts. Black et al. demonstrated that FOXF1 inhibits pulmonary fibrosis by preventing CDH2 to CDH11 cadherin switch in myofibroblasts.
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