Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany.
EMBO J. 2011 May 18;30(10):1977-89. doi: 10.1038/emboj.2011.94. Epub 2011 Apr 5.
MicroRNAs have well-established roles in eukaryotic host responses to viruses and extracellular bacterial pathogens. In contrast, microRNA responses to invasive bacteria have remained unknown. Here, we report cell type-dependent microRNA regulations upon infection of mammalian cells with the enteroinvasive pathogen, Salmonella Typhimurium. Murine macrophages strongly upregulate NF-κB associated microRNAs; strikingly, these regulations which are induced by bacterial lipopolysaccharide (LPS) occur and persist regardless of successful host invasion and/or replication, or whether an inflammatory response is mounted, suggesting that microRNAs belong to the first line of anti-bacterial defence. However, a suppression of the global immune regulator miR-155 in endotoxin-tolerant macrophages revealed that microRNA responses also depend on the status of infected cells. This study identifies the let-7 family as the common denominator of Salmonella-regulated microRNAs in macrophages and epithelial cells, and suggests that repression of let-7 relieves cytokine IL-6 and IL-10 mRNAs from negative post-transcriptional control. Our results establish a paradigm of microRNA-mediated feed-forward activation of inflammatory factors when mammalian cells are targeted by bacterial pathogens.
MicroRNAs 在真核宿主对病毒和细胞外细菌病原体的反应中具有明确的作用。相比之下，针对入侵细菌的 microRNA 反应仍然未知。在这里，我们报告了哺乳动物细胞感染肠侵袭性病原体鼠伤寒沙门氏菌时依赖于细胞类型的 microRNA 调控。鼠巨噬细胞强烈地上调 NF-κB 相关的 microRNAs；引人注目的是，这些由细菌脂多糖 (LPS) 诱导的调控无论宿主入侵和/或复制是否成功，或者是否发生炎症反应，都会发生并持续存在，表明 microRNAs 属于第一道抗菌防御。然而，内毒素耐受巨噬细胞中全局免疫调节剂 miR-155 的抑制作用表明，microRNA 反应也依赖于受感染细胞的状态。本研究确定了 let-7 家族是巨噬细胞和上皮细胞中沙门氏菌调控的 microRNAs 的共同特征，并表明 let-7 的抑制作用使细胞因子 IL-6 和 IL-10 mRNAs 免受负转录后调控。我们的结果建立了一个模式，即在哺乳动物细胞被细菌病原体靶向时，microRNA 介导的炎症因子的正反馈激活。
