Cytokine-mediated immune-cell recruitment and inflammation contribute to protection in respiratory virus infection. However, uncontrolled inflammation and the “cytokine storm” are hallmarks of immunopathology in severe infection. Cytokine storm is a broad term for a phenomenon with diverse characteristics and drivers, depending on host genetics, age, and other factors. Taking advantage of the differential use of virus-sensing systems by different cell types, we test the hypothesis that specifically blocking TLR7-dependent, immune cell–produced cytokines reduces influenza-related immunopathology. In a mouse model of severe influenza characterized by a type I interferon (IFN-I)–driven cytokine storm, TLR7 antagonist treatment leaves epithelial antiviral responses unaltered but acts through pDCs and monocytes to reduce IFN-I and other cytokines in the lung, thus ameliorating inflammation and severity. Moreover, even in the absence of IFN-I signaling, TLR7 antagonism reduces inflammation and mortality driven by monocyte-produced chemoattractants and neutrophil recruitment into the infected lung. Hence, TLR7 antagonism reduces diverse types of cytokine storm in severe influenza.

中文翻译：

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TLR7 拮抗剂限制严重流感小鼠模型中干扰素依赖性和非依赖性免疫病理学


细胞因子介导的免疫细胞募集和炎症有助于保护呼吸道病毒感染。然而，不受控制的炎症和“细胞因子风暴”是严重感染的免疫病理学特征。细胞因子风暴是一个广义术语，指具有多种特征和驱动因素的现象，具体取决于宿主遗传学、年龄和其他因素。利用不同细胞类型对病毒传感系统的不同使用，我们测试了这样的假设：特异性阻断 TLR7 依赖的免疫细胞产生的细胞因子可减少流感相关的免疫病理学。在以 I 型干扰素 (IFN-I) 驱动的细胞因子风暴为特征的严重流感小鼠模型中，TLR7 拮抗剂治疗使上皮抗病毒反应保持不变，但通过 pDC 和单核细胞发挥作用，减少肺部的 IFN-I 和其他细胞因子，从而改善炎症和严重程度。此外，即使在没有 IFN-I 信号传导的情况下，TLR7 拮抗作用也能减少单核细胞产生的趋化剂和中性粒细胞募集到受感染肺部引起的炎症和死亡率。因此，TLR7 拮抗作用可减少严重流感中多种类型的细胞因子风暴。