Control of the Inflammatory Macrophage Transcriptional Signature by miR-155.
Control of the Inflammatory Macrophage Transcriptional Signature by miR-155.
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miR-155 对炎症巨噬细胞转录特征的控制。
DOI：
10.1371/journal.pone.0159724
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Guerau-de-Arellano M
中科院分区：
文献类型：
--
作者：
Jablonski KA;Gaudet AD;Amici SA;Popovich PG;Guerau-de-Arellano M
炎性M1谱巨噬细胞保护免受感染，但可引起炎性疾病和组织损伤，而替代活化的/M2谱巨噬细胞减少炎症并促进组织修复。巨噬细胞表型的调节可能在治疗上是有益的，需要进一步了解控制巨噬细胞分化的分子程序。巨噬细胞分化的潜在机制可能是通过microRNA（miRNA），其结合信使RNA并转录后修饰基因表达、细胞表型和功能。我们假设炎症相关的miRNA，miR-155，是巨噬细胞炎症状态典型发展所必需的。miR-155在炎性M1（LPS + IFN-γ）巨噬细胞中迅速上调超过100倍，但在M2（IL-4）巨噬细胞中未上调。在miR-155敲除小鼠M1（LPS + IFN-γ）巨噬细胞中，炎症基因Inos、Il 1b和Tnfa及其相应的蛋白质或酶产物减少高达72%，但miR-155缺陷不影响M2（IL-4）巨噬细胞中M2相关基因Arg 1的表达。此外，miR-155寡核苷酸抑制剂有效抑制野生型M1（LPS + IFN-γ）巨噬细胞中的Inos和Tnfa基因表达。未刺激的和来自野生型（WT）和miR-155敲除（KO）小鼠的M1（LPS + IFN-γ）巨噬细胞的比较转录谱显示，我们先前在WT M1（LPS + IFN-γ）巨噬细胞中鉴定的标记的一半（约650个基因）依赖于miR-155。独立数据集的实时PCR证实，miR-155有助于抑制其验证的mRNA靶点Inpp 5d、Tspan 14、Ptprj和Mafb，并诱导Inos、Illb、Tnfa、Il 6和Il 12。总体而言，这些数据表明miR-155在驱动M1（LPS+ IFN-γ）巨噬细胞的炎性表型中起重要作用。
Inflammatory M1 spectrum macrophages protect from infection but can cause inflammatory disease and tissue damage, whereas alternatively activated/M2 spectrum macrophages reduce inflammation and promote tissue repair. Modulation of macrophage phenotype may be therapeutically beneficial and requires further understanding of the molecular programs that control macrophage differentiation. A potential mechanism by which macrophages differentiate may be through microRNA (miRNA), which bind to messenger RNA and post-transcriptionally modify gene expression, cell phenotype and function. We hypothesized that the inflammation-associated miRNA, miR-155, would be required for typical development of macrophage inflammatory state. miR-155 was rapidly up-regulated over 100-fold in inflammatory M1(LPS + IFN-γ), but not M2(IL-4), macrophages. Inflammatory genes Inos, Il1b and Tnfa and their corresponding protein or enzymatic products were reduced up to 72% in miR-155 knockout mouse M1(LPS + IFN-γ) macrophages, but miR-155 deficiency did not affect expression of the M2-associated gene Arg1 in M2(IL-4) macrophages. Additionally, a miR-155 oligonucleotide inhibitor efficiently suppressed Inos and Tnfa gene expression in wild-type M1(LPS + IFN-γ) macrophages. Comparative transcriptional profiling of unstimulated and M1(LPS + IFN-γ) macrophages derived from wild-type (WT) and miR-155 knockout (KO) mice revealed that half (approximately 650 genes) of the signature we previously identified in WT M1(LPS + IFN-γ) macrophages was dependent on miR-155. Real-Time PCR of independent datasets confirmed that miR-155 contributed to suppression of its validated mRNA targets Inpp5d, Tspan14, Ptprj and Mafb and induction of Inos, Il1b, Tnfa, Il6 and Il12. Overall, these data indicate that miR-155 plays an essential role in driving the inflammatory phenotype of M1(LPS+ IFN-γ) macrophages.