Labzin Larisa I, Schmidt Susanne V, Masters Seth L, Beyer Marc, Krebs Wolfgang, Klee Kathrin, Stahl Rainer, Lütjohann Dieter, Schultze Joachim L, Latz Eicke, De Nardo Dominic
Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany;
Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
J Immunol. 2015 Nov 1;195(9):4446-55. doi: 10.4049/jimmunol.1500204. Epub 2015 Sep 28.
Cytokines and IFNs downstream of innate immune pathways are critical for mounting an appropriate immune response to microbial infection. However, the expression of these inflammatory mediators is tightly regulated, as uncontrolled production can result in tissue damage and lead to chronic inflammatory conditions and autoimmune diseases. Activating transcription factor 3 (ATF3) is an important transcriptional modulator that limits the inflammatory response by controlling the expression of a number of cytokines and chemokines. However, its role in modulating IFN responses remains poorly defined. In this study, we demonstrate that ATF3 expression in macrophages is necessary for governing basal IFN-β expression, as well as the magnitude of IFN-β cytokine production following activation of innate immune receptors. We found that ATF3 acted as a transcriptional repressor and regulated IFN-β via direct binding to a previously unidentified specific regulatory site distal to the Ifnb1 promoter. Additionally, we observed that ATF3 itself is a type I IFN-inducible gene, and that ATF3 further modulates the expression of a subset of inflammatory genes downstream of IFN signaling, suggesting it constitutes a key component of an IFN negative feedback loop. Consistent with this, macrophages deficient in Atf3 showed enhanced viral clearance in lymphocytic choriomeningitis virus and vesicular stomatitis virus infection models. Our study therefore demonstrates an important role for ATF3 in modulating IFN responses in macrophages by controlling basal and inducible levels of IFNβ, as well as the expression of genes downstream of IFN signaling.
天然免疫途径下游的细胞因子和干扰素对于对微生物感染产生适当的免疫反应至关重要。然而，这些炎症介质的表达受到严格调控，因为不受控制的产生会导致组织损伤，并引发慢性炎症状态和自身免疫性疾病。激活转录因子3（ATF3）是一种重要的转录调节因子，它通过控制多种细胞因子和趋化因子的表达来限制炎症反应。然而，其在调节干扰素反应中的作用仍不清楚。在本研究中，我们证明巨噬细胞中ATF3的表达对于调控基础IFN-β表达以及天然免疫受体激活后IFN-β细胞因子产生的幅度是必要的。我们发现ATF3作为转录抑制因子，通过直接结合到Ifnb1启动子远端一个先前未鉴定的特定调控位点来调节IFN-β。此外，我们观察到ATF3本身是一种I型干扰素诱导基因，并且ATF3进一步调节干扰素信号下游一部分炎症基因的表达，这表明它构成了干扰素负反馈回路的关键组成部分。与此一致的是，在淋巴细胞性脉络丛脑膜炎病毒和水疱性口炎病毒感染模型中，Atf3缺陷的巨噬细胞显示出增强的病毒清除能力。因此，我们的研究证明了ATF3在通过控制IFNβ的基础水平和诱导水平以及干扰素信号下游基因的表达来调节巨噬细胞中干扰素反应方面的重要作用。
