Bi Jia, Zeng Xianxin, Zhao Lin, Wei Qian, Yu Lifeng, Wang Xinnan, Yu Zhaojin, Cao Yaming, Shan Fengping, Wei Minjie
Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China.
Department of Immunology, School of Basic Medical Science, China Medical university, Shenyang, Liaoning, China.
Mol Ther Nucleic Acids. 2016 Sep 27;5(9):e368. doi: 10.1038/mtna.2016.71.
Macrophages can acquire a variety of polarization status and functions: classically activated macrophages (M1 macrophages); alternatively activated macrophages (M2 macrophages). However, the molecular basis of the process is still unclear. Here, this study addresses that microRNA-181a (miR-181a) is a key molecule controlling macrophage polarization. We found that miR-181a is overexpressed in M2 macrophages than in M1 macrophages. miR-181a expression was decreased when M2 phenotype converted to M1, whereas it increased when M1 phenotype converted to M2. Overexpression of miR-181a in M1 macrophages diminished M1 phenotype expression while promoting polarization to the M2 phenotype. In contrast, knockdown of miR-181a in M2 macrophages promoted M1 polarization and diminished M2 phenotype expression. Mechanistically, Bioinformatic analysis revealed that Kruppel-like factor 6 (KLF6) and CCAAT/enhancer binding protein-α (C/EBPα) is a potential target of miR-181a and luciferase assay confirmed that KLF6 and C/EBPα translation is suppressed by miR-181a through interaction with the 3'UTR of KLF6 and C/EBPα mRNA. Further analysis showed that induction of miR-181a suppressed KLF6 and C/EBPα protein expression. Importantly, miR-181a also diminishes M2 macrophages-mediated migration and invasion capacity of tumor cells. Collectively, our results suggest that miR-181a plays a significant role in regulating macrophage polarization through directly target KLF6 and C/EBPα.
经典活化巨噬细胞（M1巨噬细胞）；替代活化巨噬细胞（M2巨噬细胞）。然而，这一过程的分子基础仍不清楚。在此，本研究指出微小RNA-181a（miR-181a）是控制巨噬细胞极化的关键分子。我们发现miR-181a在M2巨噬细胞中比在M1巨噬细胞中表达上调。当M2表型转变为M1时，miR-181a表达降低，而当M1表型转变为M2时，其表达增加。在M1巨噬细胞中过表达miR-181a可减少M1表型表达，同时促进向M2表型极化。相反，在M2巨噬细胞中敲低miR-181a可促进M1极化并减少M2表型表达。机制上，生物信息学分析显示， Kruppel样因子6（KLF6）和CCAAT/增强子结合蛋白-α（C/EBPα）是miR-181a的潜在靶标，荧光素酶检测证实miR-181a通过与KLF6和C/EBPα mRNA的3'UTR相互作用抑制KLF6和C/EBPα的翻译。进一步分析表明，miR-181a的诱导可抑制KLF6和C/EBPα蛋白表达。重要的是，miR-181a还可降低M2巨噬细胞介导的肿瘤细胞迁移和侵袭能力。总之，我们的结果表明，miR-181a通过直接靶向KLF6和C/EBPα在调节巨噬细胞极化中起重要作用。
