During viral infections, cells produce type I interferons (IFNs), which are detected by the IFNα/β receptor (IFNAR). To survive in hosts, viruses have strategies to downregulate IFN-mediated signaling. We hypothesized that macrophages, which are among the first myeloid cells to respond to viral infections, would produce a different cytokine profile if responding to ligation of pattern recognition receptors (PRRs) while IFNAR-mediated signaling was compromised. Specifically, IFNAR-mediated regulation of interleukin (IL)-1α, IL-6, IL-12, and tumor necrosis factor-α was studied in cultured murine bone marrow-derived macrophages. Since viruses like vesicular stomatitis virus can ligate PRRs such as Toll-like receptor (TLR)4 and 7, macrophages were stimulated with the TLR4 and TLR7 agonists lipopolysaccharide (LPS) or imiquimod, respectively, with or without antibody-mediated IFNAR-blockade. Cytokines and viability were assessed for 3 days poststimulation. Blocking IFNARs acutely exacerbated cytokine production by macrophages and aided their survival when they were treated with LPS. In contrast, cytokine concentrations were unaffected or slightly reduced by IFNAR blockade, but macrophages died at a greater rate when imiquimod was the stimulus. This demonstrated a differential role of IFNAR signaling in regulating PRR-induced cytokines. This suggests potential mechanisms whereby macrophages responding to viruses that inhibit type I IFN responses might contribute to excessive inflammation in some cases and inappropriately low-magnitude responses in others. This also provides a well-defined cell-based model for further dissecting the role of type I IFN signaling in macrophages responding to viral and other infections.

中文翻译：

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I 型干扰素信号在调节骨髓源性巨噬细胞中细胞因子产生和细胞存活中的作用

在病毒感染期间，细胞会产生 I 型干扰素 (IFN)，这些干扰素可被 IFN α / β受体 (IFNAR) 检测到。为了在宿主中生存，病毒具有下调 IFN 介导的信号传导的策略。我们假设，如果响应模式识别受体 (PRR) 的连接而 IFNAR 介导的信号传导受到损害，巨噬细胞是最早对病毒感染作出反应的骨髓细胞之一，它们会产生不同的细胞因子谱。具体来说，IFNAR 介导的白细胞介素 (IL)-1 α、IL-6、IL-12 和肿瘤坏死因子-α的调节在培养的小鼠骨髓来源的巨噬细胞中进行了研究。由于像水疱性口炎病毒这样的病毒可以连接 PRR，如 Toll 样受体 (TLR)4 和 7，巨噬细胞分别用 TLR4 和 TLR7 激动剂脂多糖 (LPS) 或咪喹莫特刺激，有或没有抗体介导的 IFNAR 阻断。在刺激后 3 天评估细胞因子和活力。阻断 IFNAR 会急剧加剧巨噬细胞的细胞因子产生，并在用 LPS 治疗时帮助它们存活。相比之下，IFNAR 阻断不影响或略微降低细胞因子浓度，但当咪喹莫特为刺激物时，巨噬细胞的死亡速度更快。这证明了 IFNAR 信号在调节 PRR 诱导的细胞因子中的不同作用。这表明了巨噬细胞对抑制 I 型 IFN 反应的病毒作出反应的潜在机制，在某些情况下可能会导致过度炎症，而在其他情况下可能会导致不适当的低幅度反应。这也提供了一个定义明确的基于细胞的模型，用于进一步剖析 I 型 IFN 信号在巨噬细胞对病毒和其他感染作出反应的作用。