miR-125a-5p Regulates Differential Activation of Macrophages and Inflammation
miR-125a-5p Regulates Differential Activation of Macrophages and Inflammation
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DOI：
10.1074/jbc.m112.426866
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发表时间：
2013-12-06
影响因子：
4.8
通讯作者：
Liu, Gang
中科院分区：
文献类型：
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作者：
Banerjee, Sami;Cui, Huachun;Liu, Gang
巨噬细胞活化是免疫应答中的核心事件。经历经典活化的巨噬细胞（M1巨噬细胞）具有促炎作用，而选择性活化的巨噬细胞（M2巨噬细胞）通常具有抗炎作用。微小RNA（miRNAs）在炎症反应中起重要的调节作用。然而，miRNAs响应不同环境信号调节巨噬细胞活化的方式尚未明确界定。在本研究中，我们发现M - BMM巨噬细胞（M2）比GM - BMM巨噬细胞（M1）表达更高水平的miR - 125a - 5p。通过Toll样受体2（TLR2）和Toll样受体4（TLR4）而非通过Toll样受体3刺激巨噬细胞可增强miR - 125a - 5p的表达。TLR2/4活化后miR - 125a - 5p的上调需要接头蛋白髓样分化因子88（MYD88），而不需要Toll/IL - 1受体结构域包含的接头诱导干扰素β（TRIF）。miR - 125a - 5p的过表达减少了脂多糖（LPS）诱导的M1表型表达，但促进了白细胞介素 - 4（IL - 4）诱导的M2标志物表达。相反，miR - 125a - 5p的敲低促进了M1极化并减少了IL - 4诱导的M2标志物表达。我们发现miR - 125a - 5p靶向Krüppel样因子13（KLF13），这是一种在T淋巴细胞活化和炎症中具有重要作用的转录因子。KLF13的敲低对M1活化的影响与miR - 125a - 5p过表达相似。此外，miR - 125a - 5p调节巨噬细胞的吞噬和杀菌活性。我们的数据表明，miR - 125a - 5p在抑制巨噬细胞的经典活化同时促进选择性活化方面具有重要作用。
Macrophage activation is a central event in immune responses. Macrophages undergoing classical activation (M1 macrophages) are proinflammatory, whereas alternatively activated macrophages (M2 macrophages) are generally anti-inflammatory. miRNAs play important regulatory roles in inflammatory response. However, the manner in which miRNAs regulate macrophage activation in response to different environmental cues has not been well defined. In this study, we found that M-BMM macrophages (M2) express greater levels of miR-125a-5p than do GM-BMM macrophages (M1). Stimulation of macrophages through TLR2 and TLR4 but not through TLR3 enhanced miR-125a-5p expression. Up-regulation of miR-125a-5p after TLR2/4 activation requires the adaptor MYD88 but not TRIF. Overexpression of miR-125a-5p diminished M1 phenotype expression induced by LPS but promoted M2 marker expression induced by IL-4. In contrast, knockdown of miR-125a-5p promoted M1 polarization and diminished IL-4-induced M2 marker expression. We found that miR-125a-5p targets KLF13, a transcriptional factor that has an important role in T lymphocyte activation and inflammation. KLF13 knockdown had similar effects on M1 activation as did miR-125a-5p overexpression. In addition, miR-125a-5p regulates phagocytic and bactericidal activities of macrophages. Our data suggest that miR-125a-5p has an important role in suppressing classical activation of macrophages while promoting alternative activation.