Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201; and.
Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104.
J Immunol. 2020 Apr 15;204(8):2192-2202. doi: 10.4049/jimmunol.1900912. Epub 2020 Mar 9.
Type I and III IFNs play diverse roles in bacterial infections, being protective for some but deleterious for others. Using RNA-sequencing transcriptomics we investigated lung gene expression responses to infection in adult mice, revealing that type I and III IFN pathways may play an important role in promoting inflammatory responses. In infected mice, lung type I/III IFN responses correlated with increased proinflammatory cytokine expression and with lung inflammatory pathology. In mutant mice with increased type I IFN receptor (IFNAR) signaling, infection exacerbated lung inflammatory pathology, whereas knockout mice with defects in type I IFN signaling had lower levels of lung inflammation than wild-type mice. Curiously, -infected IFNAR1 knockout mice had wild-type levels of lung inflammatory pathology. However, in response to infection these mice had increased levels of type III IFN expression, neutralization of which reduced lung inflammation. In support of this finding, -infected mice with a knockout mutation in the type III IFN receptor (IFNLR1) and double IFNAR1/IFNLR1 knockout mutant mice had reduced lung inflammatory pathology compared with that in wild-type mice, indicating that type III IFN exacerbates lung inflammation. In marked contrast, infant mice did not upregulate type I or III IFNs in response to infection and were protected from lethal infection by increased type I IFN signaling. These results indicate age-dependent effects of type I/III IFN signaling during infection and suggest that these pathways represent targets for therapeutic intervention in pertussis.
I 型和 III 型干扰素在细菌感染中发挥着多样化的作用，对某些感染具有保护作用，而对另一些感染则具有损害作用。我们使用 RNA 测序转录组学方法研究了成人肺部对 感染的基因表达反应，揭示了 I 型和 III 型 IFN 途径可能在促进炎症反应方面发挥着重要作用。在感染的小鼠中，肺部 I 型/III 型 IFN 反应与促炎细胞因子表达的增加以及肺部炎症病理相关。在 IFNAR1 信号转导增强的突变小鼠中， 感染加剧了肺部炎症病理，而 IFN 信号转导缺陷的 I 型 IFN 敲除小鼠的肺部炎症水平低于野生型小鼠。奇怪的是，IFNAR1 敲除的 感染小鼠肺部炎症病理与野生型小鼠相当。然而，这些小鼠在感染后表达了更高水平的 III 型 IFN，中和该 IFN 可降低肺部炎症。支持这一发现的是，III 型 IFN 受体（IFNLR1）敲除突变的 感染小鼠和 IFNAR1/IFNLR1 双重敲除突变的小鼠与野生型小鼠相比，肺部炎症病理减轻，表明 III 型 IFN 加剧了肺部炎症。相比之下，感染的婴儿小鼠不会因 感染而上调 I 型或 III 型 IFN，并且通过增加 I 型 IFN 信号转导而免受致死性感染的保护。这些结果表明 I 型/III 型 IFN 信号转导在 感染期间存在年龄依赖性效应，并表明这些途径是百日咳治疗干预的潜在靶点。
