Toll-like receptor 7 (TLR7) is an endosomal Pathogen-Associated Molecular Pattern (PAMP) receptor that senses single-stranded RNA (ssRNA) and whose engagement results in the production of type I IFN and pro-inflammatory cytokines upon viral exposure. Recent genetic studies have established that a dysfunctional TLR7-initiated signaling is directly linked to the development of inflammatory responses. We present evidences that TLR7 is preferentially expressed by monocyte-derived macrophages generated in the presence of M-CSF (M-MØ). We now show that TLR7 activation in M-MØ triggers a weak MAPK, NFκB and STAT1 activation and results in low production of type I IFN. Of note, TLR7 engagement re-programs MAFB+ M-MØ towards a pro-inflammatory transcriptional profile characterized by the expression of neutrophil-attracting chemokines (CXCL1-3, CXCL5, CXCL8), whose expression is dependent on the transcription factors MAFB and AhR. Moreover, TLR7-activated M-MØ display enhanced pro-inflammatory responses and a stronger production of neutrophil-attracting chemokines upon secondary stimulation. As aberrant TLR7 signaling and enhanced pulmonary neutrophil/lymphocyte ratio associate with impaired resolution of virus-induced inflammatory responses, these results suggest that targeting macrophage TLR7 might be a therapeutic strategy for viral infections where monocyte-derived macrophages exhibit a pathogenic role.


中文翻译：

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M-CSF 依赖性单核细胞来源的人巨噬细胞中 TLR7 的激活增强炎症反应并促进中性粒细胞募集

Toll 样受体 7 (TLR7) 是一种内体病原体相关分子模式 (PAMP) 受体，可感知单链 RNA (ssRNA)，其参与会导致病毒暴露后产生 I 型干扰素和促炎细胞因子。最近的遗传学研究表明，功能失调的 TLR7 启动信号传导与炎症反应的发生直接相关。我们提供的证据表明，TLR7 优先由在 M-CSF (M-MØ) 存在下产生的单核细胞衍生的巨噬细胞表达。我们现在表明，M-MØ 中的 TLR7 激活会触发较弱的 MAPK、NFκB 和 STAT1 激活，并导致 I 型 IFN 的低产量。值得注意的是，TLR7 参与将 MAFB+ M-MØ 重新编程为促炎转录谱，其特征是中性粒细胞吸引趋化因子（CXCL1-3、CXCL5、CXCL8)，其表达依赖于转录因子 MAFB 和 AhR。此外，TLR7 激活的 M-MØ 在二次刺激后表现出增强的促炎反应和更强的中性粒细胞吸引趋化因子的产生。由于异常的 TLR7 信号传导和肺中性粒细胞/淋巴细胞比率的增强与病毒诱导的炎症反应的分辨率受损相关，因此这些结果表明，靶向巨噬细胞 TLR7 可能是单核细胞来源的巨噬细胞表现出致病作用的病毒感染的治疗策略。