miR-142-5p and miR-130a-3p are regulated by IL-4 and IL-13 and control profibrogenic macrophage program.
miR-142-5p and miR-130a-3p are regulated by IL-4 and IL-13 and control profibrogenic macrophage program.
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miR-142-5p 和 miR-130a-3p 受 IL-4 和 IL-13 调节，并控制促纤维化巨噬细胞程序。
DOI：
10.1038/ncomms9523
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发表时间：
2015-10-05
影响因子：
16.6
通讯作者：
Song E
中科院分区：
文献类型：
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作者：
Su S;Zhao Q;He C;Huang D;Liu J;Chen F;Chen J;Liao JY;Cui X;Zeng Y;Yao H;Su F;Liu Q;Jiang S;Song E
巨噬细胞在组织纤维化中起关键作用，这是许多终末期慢性炎症性疾病的发病机制的基础。microRNA是免疫细胞功能的关键调节因子，但它们在巨噬细胞纤维化中的作用尚未被表征。在这里，我们发现IL-4和IL-13诱导巨噬细胞中的miR-142- 5 p并下调miR-130 a-3 p;这些变化维持了巨噬细胞的促纤维化作用。在体外，miR-142- 5 p通过靶向其负调控因子SOCS 1来模拟STAT 6磷酸化。阻断miR-130 a可缓解其对协调STAT 6信号传导的PPARγ的抑制。在体内，用锁核酸修饰的寡核苷酸抑制miR-142- 5 p并增加miR-130 a-3 p表达可抑制小鼠中CCL 4诱导的肝纤维化和博来霉素诱导的肺纤维化。此外，来自肝硬化和特发性肺纤维化患者的组织样品的巨噬细胞显示增加的miR-142- 5 p和减少的miR-130 a-3 p表达。因此，miR-142- 5 p和miR-130 a-3 p调节慢性炎症中巨噬细胞促纤维化基因的表达。 成纤维细胞活性由组织巨噬细胞调节。在这里，作者表明巨噬细胞中由IL-4和IL-13调节的两种miRNA靶向SOCS 1和PPARγ，并在体外和体内调节促纤维化巨噬细胞程序，并且在纤维化中发现这些miRNA的改变。
Macrophages play a pivotal role in tissue fibrogenesis, which underlies the pathogenesis of many end-stage chronic inflammatory diseases. MicroRNAs are key regulators of immune cell functions, but their roles in macrophage's fibrogenesis have not been characterized. Here we show that IL-4 and IL-13 induce miR-142-5p and downregulate miR-130a-3p in macrophages; these changes sustain the profibrogenic effect of macrophages. In vitro, miR-142-5p mimic prolongs STAT6 phosphorylation by targeting its negative regulator, SOCS1. Blocking miR-130a relieves its inhibition of PPARγ, which coordinates STAT6 signalling. In vivo, inhibiting miR-142-5p and increasing miR-130a-3p expression with locked nucleic acid-modified oligonucleotides inhibits CCL4-induced liver fibrosis and bleomycin-induced lung fibrosis in mice. Furthermore, macrophages from the tissue samples of patients with liver cirrhosis and idiopathic pulmonary fibrosis display increased miR-142-5p and decreased miR-130a-3p expression. Therefore, miR-142-5p and miR-130a-3p regulate macrophage profibrogenic gene expression in chronic inflammation. Fibroblast activity is regulated by tissue macrophages. Here the authors show that two miRNAs regulated by IL-4 and IL-13 in macrophages target SOCS1 and PPARγ and modulate profibrogenic macrophage program in vitro and in vivo, and that alterations of these miRNAs are found in fibrosis.