National Key Laboratory of Medical Molecular Biology, Department of Immunology, Chinese Academy of Medical Sciences, Beijing 100005, China;
J Immunol. 2013 Oct 1;191(7):3896-904. doi: 10.4049/jimmunol.1203450. Epub 2013 Aug 26.
Innate immune responses must be tightly regulated to avoid overactivation and subsequent inflammatory damage to host tissue while eliminating invading pathogens. IL-10 is a crucial suppressor of inflammatory responses and its expression is under precise regulation involving complex regulatory networks and multiple feedback loops. MicroRNAs are now emerging as critical regulators in immune response. Our previous work showed that miR-143/145 cluster was markedly downregulated in macrophages upon vesicular stomatitis virus infection. However, the particular role of miR-143/145 cluster in the regulation of innate immune response remains unknown. In this study, we found that miR-143/145 cluster expression was also downregulated dramatically by TLR signals in macrophages, which was dependent on the subsequent type I IFN (IFN-I) production and downstream IFN-I receptor-JAK1-STAT1 signal cascade. Further studies demonstrated that miR-145, but not miR-143, promoted IL-10 expression in TLR4-triggered macrophages through directly targeting the epigenetic Il10 gene silencer histone deacetylase 11. Therefore, we demonstrate that miR-145, downregulated by IFN-I, targets histone deacetylase 11 to promote innate IL-10 expression in macrophages. Our findings suggest a new IFN-I-mediated negative feedback loop in the fine-tuning of innate IL-10 production that creates precise coordination of innate immune responses.
先天免疫反应必须受到严格的调控，以避免过度激活和随后的宿主组织炎症损伤，同时消除入侵的病原体。IL-10 是炎症反应的关键抑制剂，其表达受到精确的调控，涉及复杂的调控网络和多个反馈回路。miRNAs 现在作为免疫反应的关键调节剂而出现。我们之前的工作表明，在水疱性口炎病毒感染后，巨噬细胞中的 miR-143/145 簇显著下调。然而，miR-143/145 簇在先天免疫反应调控中的特定作用仍然未知。在这项研究中，我们发现 TLR 信号也能显著下调巨噬细胞中的 miR-143/145 簇表达，这依赖于随后的 I 型干扰素（IFN-I）的产生和下游 IFN-I 受体-JAK1-STAT1 信号级联。进一步的研究表明，miR-145 而不是 miR-143 通过直接靶向表观遗传 Il10 基因沉默组蛋白去乙酰化酶 11 促进 TLR4 触发的巨噬细胞中 IL-10 的表达。因此，我们证明了由 IFN-I 下调的 miR-145 通过靶向组蛋白去乙酰化酶 11 来促进巨噬细胞中先天的 IL-10 表达。我们的发现表明，IFN-I 介导的负反馈回路在先天 IL-10 产生的精细调控中创造了先天免疫反应的精确协调。
