Ni Bin, Rajaram Murugesan V S, Lafuse William P, Landes Michelle B, Schlesinger Larry S
Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210; Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210; and Center for Microbial Interface Biology, The Ohio State University, Columbus, OH 43210.
Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210; and Center for Microbial Interface Biology, The Ohio State University, Columbus, OH 43210.
J Immunol. 2014 Nov 1;193(9):4537-47. doi: 10.4049/jimmunol.1400124. Epub 2014 Sep 24.
IFN-γ-activated macrophages play an essential role in controlling intracellular pathogens; however, macrophages also serve as the cellular home for the intracellular pathogen Mycobacterium tuberculosis. Based on previous evidence that M. tuberculosis can modulate host microRNA (miRNA) expression, we examined the miRNA expression profile of M. tuberculosis-infected primary human macrophages. We identified 31 differentially expressed miRNAs in primary human macrophages during M. tuberculosis infection by NanoString and confirmed our findings by quantitative real-time RT-PCR. In addition, we determined a role for two miRNAs upregulated upon M. tuberculosis infection, miR-132 and miR-26a, as negative regulators of transcriptional coactivator p300, a component of the IFN-γ signaling cascade. Knockdown expression of miR-132 and miR-26a increased p300 protein levels and improved transcriptional, translational, and functional responses to IFN-γ in human macrophages. Collectively, these data validate p300 as a target of miR-132 and miR-26a, and demonstrate a mechanism by which M. tuberculosis can limit macrophage responses to IFN-γ by altering host miRNA expression.
γ干扰素激活的巨噬细胞在控制细胞内病原体方面发挥着重要作用；然而，巨噬细胞也是细胞内病原体结核分枝杆菌的细胞宿主。基于先前关于结核分枝杆菌可调节宿主微小RNA（miRNA）表达的证据，我们检测了结核分枝杆菌感染的原代人巨噬细胞的miRNA表达谱。我们通过NanoString技术鉴定出原代人巨噬细胞在结核分枝杆菌感染期间有31种差异表达的miRNA，并通过定量实时逆转录-聚合酶链反应证实了我们的发现。此外，我们确定了结核分枝杆菌感染后上调的两种miRNA，即miR-132和miR-26a，作为转录共激活因子p300（γ干扰素信号级联反应的一个组成部分）的负调节因子的作用。敲低miR-132和miR-26a的表达可增加人巨噬细胞中p300蛋白水平，并改善对γ干扰素的转录、翻译和功能反应。总体而言，这些数据验证了p300是miR-132和miR-26a的靶标，并证明了结核分枝杆菌可通过改变宿主miRNA表达来限制巨噬细胞对γ干扰素反应的一种机制。
