Type I IFN Inhibits Innate IL-10 Production in Macrophages through Histone Deacetylase 11 by Downregulating MicroRNA-145
Type I IFN Inhibits Innate IL-10 Production in Macrophages through Histone Deacetylase 11 by Downregulating MicroRNA-145
复制标题
I 型 IFN 通过下调 MicroRNA-145，通过组蛋白脱乙酰酶 11 抑制巨噬细胞中先天性 IL-10 的产生
DOI：
10.4049/jimmunol.1203450
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发表时间：
2013-10-01
影响因子：
4.4
通讯作者：
Cao, Xuetao
中科院分区：
文献类型：
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作者：
Lin, Li;Hou, Jin;Cao, Xuetao
必须严格调节先天免疫反应，以避免过度激活和随后对宿主组织的炎症损伤，同时消除入侵的病原体。IL-10是炎症反应的重要抑制因子，其表达受到复杂的调控网络和多个反馈回路的精确调控。目前，microrna在免疫反应中已成为重要的调节因子。我们之前的研究表明，在水泡性口炎病毒感染后，巨噬细胞中miR-143/145簇明显下调。然而，miR-143/145簇在先天免疫反应调控中的具体作用尚不清楚。在本研究中，我们发现巨噬细胞中miR-143/145簇表达也被TLR信号显著下调，这依赖于随后的I型IFN （IFN-I）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基因沉默者组蛋白去乙酰化酶11，促进了tlr4触发的巨噬细胞中IL-10的表达。因此，我们证明被IFN-I下调的miR-145靶向组蛋白去乙酰化酶11，促进巨噬细胞中IL-10的先天表达。我们的研究结果表明，在先天IL-10产生的微调中，存在一种新的ifn - i介导的负反馈回路，该回路可创建先天免疫反应的精确协调。
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.