OBJECTIVE Peripheral blood mononuclear cells (PBMCs) in systemic lupus erythematosus (SLE) patients exhibit a gene expression program (interferon [IFN] signature) that is attributed to overproduction of type I IFNs by plasmacytoid dendritic cells. Type I IFNs have been thought to play a role in the pathogenesis of SLE. This study was undertaken to examine an unexpected influence of monocyte/macrophages on the IFN signature. METHODS Proinflammatory (classic) and antiinflammatory (nonclassic) monocyte/macrophages were sorted from mice and analyzed by RNA sequencing and quantitative polymerase chain reaction (qPCR). Type I IFN-α/β/ω receptor (IFNAR-1) expression was determined by qPCR and flow cytometry. Macrophages were stimulated in vitro with IFNα, and pSTAT1was measured. RESULTS Transcriptional profiling of peritoneal macrophages from mice with pristane-induced SLE unexpectedly indicated a strong IFN signature in classic, but not nonclassic, monocyte/macrophages exposed to the same type I IFN concentrations. Ifnar1 messenger RNA and IFNAR surface staining were higher in classic monocyte/macrophages versus nonclassic monocyte/macrophages (P < 0.0001 and P < 0.05, respectively, by Student's t-test). Nonclassic monocyte/macrophages were also relatively insensitive to IFNα-driven STAT1 phosphorylation. Humans exhibited a similar pattern: higher IFNAR expression (P < 0.0001 by Student's t-test) and IFNα-stimulated gene expression (P < 0.01 by paired Wilcoxon's rank sum test) in classic monocyte/macrophages and lower levels in nonclassic monocyte/macrophages. CONCLUSION This study revealed that the relative abundance of different monocyte/macrophage subsets helps determine the magnitude of the IFN signature. Responsiveness to IFNα signaling reflects differences in IFNAR expression in classic (high IFNAR) compared to nonclassic (low IFNAR) monocyte/macrophages. Thus, the IFN signature depends on both type I IFN production and the responsiveness of monocyte/macrophages to IFNAR signaling.

中文翻译：

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单核细胞和巨噬细胞亚群对干扰素的差异反应。

目的系统性红斑狼疮（SLE）患者的外周血单个核细胞（PBMC）表现出基因表达程序（干扰素[IFN]签名），这归因于浆细胞样树突状细胞过量产生I型干扰素。I型IFN被认为在SLE的发病机理中起作用。进行这项研究以检查单核细胞/巨噬细胞对IFN标记的意外影响。方法从小鼠中分离出促炎性（经典）和抗炎性（非经典）单核细胞/巨噬细胞，并通过RNA测序和定量聚合酶链反应（qPCR）进行分析。通过qPCR和流式细胞术确定I型IFN-α/β/ω受体（IFNAR-1）的表达。在体外用IFNα刺激巨噬细胞，并测量pSTAT1。结果p烷诱导的SLE小鼠的腹膜巨噬细胞的转录谱出乎意料地表明，在暴露于相同I型IFN浓度的经典（但非经典）单核细胞/巨噬细胞中，IFN信号很强。经典单核细胞/巨噬细胞的Ifnar1 Messenger RNA和IFNAR表面染色高于非经典单核细胞/巨噬细胞（根据Student's t检验，分别为P <0.0001和P <0.05）。非经典单核细胞/巨噬细胞对IFNα驱动的STAT1磷酸化也相对不敏感。人类表现出相似的模式：经典单核/巨噬细胞中更高的IFNAR表达（Student's t检验P <0.0001）和IFNα刺激的基因表达（成对的Wilcoxon秩和检验P <0.01），而非经典单核细胞/巨噬细胞水平更低。结论这项研究表明，不同单核细胞/巨噬细胞亚群的相对丰度有助于确定IFN信号的强度。对IFNα信号的反应性反映了与非经典（低IFNAR）单核细胞/巨噬细胞相比，经典（高IFNAR）中IFNAR表达的差异。因此，IFN标记取决于I型IFN产生和单核细胞/巨噬细胞对IFNAR信号传导的响应性。