Plasmacytoid dendritic cells (DCs) are reported to induce robust type‐I interferon (IFN) response, whereas cDC1 DCs develop moderate type‐I IFN response upon TLR9 stimulation. It is very interesting to understand how this signaling under TLR9 is tightly regulated for the induction of type‐I IFNs. Here, we report co‐repressor protein NCoR1 as the major factor fine‐tuning the signaling pathways regulating IFN‐β expression under TLR9 in cDC1 DCs. We found that NCoR1 knockdown induced a robust IFN‐β‐mediated antiviral response upon TLR9 activation in cDC1 DCs. At the molecular level, we showed that NCoR1 directly repressed MyD88‐IRF7 signaling axis in cDC1 cells. Therefore, NCoR1 depletion enhanced pIRF7 levels, IFN‐β secretion, and downstream pSTAT1‐pSTAT2 signaling, leading to sustained induction of IFN stimulatory genes. Integrative genomic analysis depicted strong enrichment of an antiviral gene‐module in CpG‐activated NCoR1 knockdown DCs upon TLR9 activation. Moreover, we confirmed our findings in primary DCs derived from splenocytes of WT and NCoR1 DC^−/− animals, which showed protection from Sendai and Vesicular Stomatitis viruses upon CpG activation. Ultimately, we identified that NCoR1–HDAC3 complex is involved in repressing the type‐I IFN response in cDC1 DCs.

中文翻译：

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NCoR1通过直接在TLR9下调节Myd88-IRF7轴来微调cDC1树突状细胞中的I型IFN反应。

据报道，浆细胞样树突状细胞（DC）诱导强烈的I型干扰素（IFN）反应，而cDC1 DC在TLR9刺激后发展为中等I型IFN反应。了解如何严格调控TLR9下的这种信号传导诱导I型IFN的作用非常有趣。在这里，我们报道了共抑制蛋白NCoR1是微调cDC1 DC中TLR9下调节IFN-β表达的信号通路的主要因素。我们发现，在cDC1 DC中TLR9激活后，NCoR1敲低会诱导强烈的IFN-β介导的抗病毒反应。在分子水平上，我们表明NCoR1直接抑制cDC1细胞中的MyD88-IRF7信号轴。因此，NCoR1耗竭会增强pIRF7水平，IFN-β分泌和下游pSTAT1-pSTAT2信号传导，从而持续诱导IFN刺激基因。综合基因组学分析显示，TLR9激活后，CpG激活的NCoR1敲低DC中抗病毒基因模块的大量富集。此外，我们证实了我们在WT和NCoR1 DC脾细胞衍生的原发DC中的发现^-/-动物，其在CpG激活后显示出对仙台和水泡性口腔炎病毒的保护作用。最终，我们确定了NCoR1-HDAC3复合体参与抑制cDC1 DC中的I型IFN应答。