IRF-3, IRF-5, and IRF-7 coordinately regulate the type I IFN response in myeloid dendritic cells downstream of MAVS signaling.
IRF-3, IRF-5, and IRF-7 coordinately regulate the type I IFN response in myeloid dendritic cells downstream of MAVS signaling.
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DOI：
10.1371/journal.ppat.1003118
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发表时间：
2013-01
期刊：
影响因子：
6.7
通讯作者：
Diamond MS
中科院分区：
文献类型：
--
作者：
Lazear HM;Lancaster A;Wilkins C;Suthar MS;Huang A;Vick SC;Clepper L;Thackray L;Brassil MM;Virgin HW;Nikolich-Zugich J;Moses AV;Gale M Jr;Früh K;Diamond MS
虽然转录因子IRF-3和IRF-7被认为是I型干扰素（IFN）诱导和IFN刺激基因（ISG）表达的主要调节因子，但Irf 3 −/−× Irf 7 −/−双敲除（DKO）骨髓树突状细胞（mDC）在病毒感染后产生相对正常水平的IFN-β。我们产生了Irf 3 −/−× Irf 5 −/−× Irf 7 −/−三重敲除（TKO）小鼠，以测试IRF-5是否是mDC中IFN-β和ISG残留诱导的来源。在两种不相关的正义RNA病毒（西尼罗河病毒（WNV）和鼠诺如病毒）的发病机制研究中，TKO小鼠的死亡率高于DKO小鼠，等于或接近缺乏I型IFN受体（Ifnar−/−）的小鼠。在离体研究中，在WNV感染或暴露于Toll样受体激动剂后，TKO mDC不能产生IFN-β或表达ISG。相反，这种反应在WNV感染后的TKO巨噬细胞中持续存在。为了确定IRF调控的基因特征，我们对来自野生型（WT）、DKO、TKO或Ifnar−/−小鼠以及缺乏RIG-I样受体衔接蛋白MAVS的小鼠的WNV感染的mDC进行了微阵列分析。尽管DKO mDC中的基因诱导模式与WT细胞相似，但值得注意的是，在TKO或Mavs−/− mDC中几乎没有检测到ISG诱导。TKO和Mavs−/−反应的相对等效性表明MAVS主要调节mDC中的ISG诱导。此外，我们发现MAVS依赖性诱导ISG可以通过IRF-5依赖性但IRF-3和IRF-7独立的途径发生。我们的研究结果建立IRF-3，-5，和-7作为关键的转录因子，负责介导I型IFN和ISG反应在mDC在WNV感染，并提出了一种新的MAVS和IRF-5之间的信号联系。宿主病原体传感器，包括Toll样受体和RIG-I样受体（RLR）家族的那些，检测细胞中的病毒感染。通过这些受体的信号传导触发I型干扰素（IFN）和IFN刺激基因（ISG）的表达，部分通过转录因子的IRF家族。先前对西尼罗河病毒（WNV）的研究表明，IRF-3和IRF-7控制成纤维细胞和神经元中的IFN表达，而巨噬细胞和髓样树突状细胞（mDC）在没有IRF-3和IRF-7的情况下仍能诱导IFN-β。在目前的研究中，我们产生了Irf 3 −/−× Irf 5 −/−× Irf 7 −/−（TKO）小鼠，以表征特异性IRF转录因子对细胞和小鼠中响应于WNV感染的IFN和ISG诱导的贡献。我们发现IFN和ISG的诱导在TKO mDC中基本上被消除，但在TKO巨噬细胞中持续。由于IFN和ISG诱导在缺乏MAVS（RLR信号传导的关键介质）的mDC中也不存在，因此我们的结果表明IRF-5和MAVS之间存在新的信号传导联系。本研究建立了负责mDC中IFN诱导的分子通路，并表明IRF-5和RLR信号通路之间存在串扰。
Although the transcription factors IRF-3 and IRF-7 are considered master regulators of type I interferon (IFN) induction and IFN stimulated gene (ISG) expression, Irf3−/−×Irf7−/− double knockout (DKO) myeloid dendritic cells (mDC) produce relatively normal levels of IFN-β after viral infection. We generated Irf3−/−×Irf5−/−×Irf7−/− triple knockout (TKO) mice to test whether IRF-5 was the source of the residual induction of IFN-β and ISGs in mDCs. In pathogenesis studies with two unrelated positive-sense RNA viruses (West Nile virus (WNV) and murine norovirus), TKO mice succumbed at rates greater than DKO mice and equal to or approaching those of mice lacking the type I IFN receptor (Ifnar−/−). In ex vivo studies, after WNV infection or exposure to Toll-like receptor agonists, TKO mDCs failed to produce IFN-β or express ISGs. In contrast, this response was sustained in TKO macrophages following WNV infection. To define IRF-regulated gene signatures, we performed microarray analysis on WNV-infected mDC from wild type (WT), DKO, TKO, or Ifnar−/− mice, as well as from mice lacking the RIG-I like receptor adaptor protein MAVS. Whereas the gene induction pattern in DKO mDC was similar to WT cells, remarkably, almost no ISG induction was detected in TKO or Mavs−/− mDC. The relative equivalence of TKO and Mavs−/− responses suggested that MAVS dominantly regulates ISG induction in mDC. Moreover, we showed that MAVS-dependent induction of ISGs can occur through an IRF-5-dependent yet IRF-3 and IRF-7-independent pathway. Our results establish IRF-3, -5, and -7 as the key transcription factors responsible for mediating the type I IFN and ISG response in mDC during WNV infection and suggest a novel signaling link between MAVS and IRF-5. Host pathogen sensors, including those of the Toll-like receptor and RIG-I like receptor (RLR) families, detect viral infection in cells. Signaling through these receptors triggers expression of type I interferon (IFN) and IFN-stimulated genes (ISGs), in part through the IRF family of transcription factors. Previous studies with West Nile virus (WNV) showed that IRF-3 and IRF-7 control IFN expression in fibroblasts and neurons, whereas macrophages and myeloid dendritic cells (mDC) retained the ability to induce IFN-β without IRF-3 and IRF-7. In the current study, we generated Irf3−/−×Irf5−/−×Irf7−/− (TKO) mice to characterize the contributions of specific IRF transcription factors to IFN and ISG induction in response to WNV infection in cells and in mice. We found that induction of IFN and ISGs was largely abolished in TKO mDC, but sustained in TKO macrophages. Because IFN and ISG induction also was absent in mDC lacking MAVS, a key mediator of RLR signaling, our results suggest a novel signaling link between IRF-5 and MAVS. This study establishes the molecular pathways responsible for IFN induction in mDC and suggests a cross-talk between IRF-5 and RLR signaling pathways.
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