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Regulation of progenitor cell proliferation and granulocyte function by microRNA-223

机译：microRNA-223对祖细胞增殖和粒细胞功能的调节

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摘要

MicroRNAs are abundant in animal genomes and have been predicted to have important roles in a broad range of gene expression programmes. Despite this prominence, there is a dearth of functional knowledge regarding individual mammalian microRNAs. Using a loss-of-function allele in mice, we report here that the myeloid-specific microRNA-223 (miR-223) negatively regulates progenitor proliferation and granulocyte differentiation and activation. miR-223 (also called Mirn223) mutant mice have an expanded granulocytic compartment resulting from a cell-autonomous increase in the number of granulocyte progenitors. We show that Mef2c, a transcription factor that promotes myeloid progenitor proliferation, is a target of miR-223, and that genetic ablation of Mef2c suppresses progenitor expansion and corrects the neutrophilic phenotype in miR-223 null mice. In addition, granulocytes lacking miR-223 are hypermature, hypersensitive to activating stimuli and display increased fungicidal activity. As a consequence of this neutrophil hyperactivity, miR-223 mutant mice spontaneously develop inflammatory lung pathology and exhibit exaggerated tissue destruction after endotoxin challenge. Our data support a model in which miR-223 acts as a fine-tuner of granulocyte production and the inflammatory response.
机译：MicroRNA在动物基因组中含量很高，据预测在广泛的基因表达程序中具有重要作用。尽管有这样的突出，但是关于单个哺乳动物微RNA的功能性知识仍然匮乏。在小鼠中使用功能丧失的等位基因，我们在这里报告髓样特异性microRNA-223（miR-223）负调节祖细胞的增殖以及粒细胞的分化和激活。 miR-223（也称为Mirn223）突变小鼠的粒细胞腔室扩大，是由于粒细胞祖细胞数量的细胞自主增加所致。我们显示，Mef2c，一个促进髓样祖细胞增殖的转录因子，是miR-223的靶标，Mef2c的基因消融抑制了祖细胞的扩增，并纠正了miR-223空小鼠的嗜中性表型。此外，缺乏miR-223的粒细胞过成熟，对激活刺激高度敏感，并显示出增强的杀真菌活性。这种嗜中性粒细胞过度活跃的结果是，miR-223突变小鼠自发发展为炎症性肺部病理，并在内毒素攻击后表现出夸张的组织破坏。我们的数据支持其中miR-223充当粒细胞产生和炎症反应的微调器的模型。

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