Myeloid-derived suppressor cells (MDSCs) contribute to high mortality rates during sepsis, but how sepsis induces MDSCs is unclear. Previously we reported that microRNA (miR)-21 and miR-181b reprogram MDSCs in septic mice by increasing levels of DNA binding transcription factor, nuclear factor 1 (NFI-A). Here, we provide evidence that miR-21 and miR-181b stabilize NFI-A mRNA and increase NFI-A protein levels by recruiting RNA-binding proteins HuR and Ago1 to its 3′ untranslated region (3′UTR). We also find that the NFI-A GU-rich element (GRE)-binding protein CUGBP1 counters miR-21 and miR-181b dependent NFI-A mRNA stabilization and decreases protein production by replacing 3′UTR bound Ago1 with Ago2. We confirmed the miR-21 and miR-181b dependent reprogramming pathway in MDSCs transfected with a luciferase reporter construct containing an NFI-A 3′UTR fragment with point mutations in the miRNA binding sites. These results suggest that targeting NFI-A in MDSCs during sepsis may enhance resistance to uncontrolled infection.

骨髓来源的抑制细胞（MDSC）有助于败血症期间的高死亡率，但尚不清楚败血症如何诱导MDSC。以前我们报道过，microRNA（miR）-21和miR-181b通过增加DNA结合转录因子核因子1（NFI-A）的水平来对败血症小鼠的MDSC进行重新编程。在这里，我们提供的证据表明，miR-21和miR-181b通过将RNA结合蛋白HuR和Ago1募集到其3'非翻译区（3'UTR）来稳定NFI-A mRNA并增加NFI-A蛋白水平。我们还发现，富含NFI-A GU的元素（GRE）结合蛋白CUGBP1可抵抗miR-21和miR-181b依赖的NFI-A mRNA稳定，并通过将3'UTR结合的Ago1替换为Ago2来降低蛋白质产量。我们证实转染了萤光素酶报告基因构建体的MDSC中miR-21和miR-181b依赖的重编程途径，该构建体包含一个在miRNA结合位点具有点突变的NFI-A 3'UTR片段。这些结果表明，在脓毒症中靶向MDSC中的NFI-A可能会增强对不受控制的感染的抵抗力。