Abstract：
Excessive or persistent inflammation may have detrimental effects on lung structure and function. Currently, our understanding of conserved host mechanisms that control the inflammatory response remains incompletely understood. In this study, we investigated the role of type I interferon signaling in the inflammatory response against diverse clinically relevant stimuli. Using mice deficient in type I interferon signaling (IFNAR1-/-), we demonstrate that the absence of interferon signaling resulted in a robust and persistent inflammatory response against Pseudomonas aeruginosa, lipopolysaccharide, and chemotherapeutic agent bleomycin. The elevated inflammatory response in IFNAR1-/- mice was manifested as elevated myeloid cells, such as macrophages and neutrophils, in the bronchoalveolar lavage. The inflammatory cell response in the IFNAR1-/- mice persisted to 14 days and there is impaired recovery and fibrotic remodeling of the lung in IFNAR1-/- mice after bleomycin injury. In the Pseudomonas infection model, the elevated inflammatory cell response led to improved bacterial clearance in IFNAR1-/- mice, although there was similar lung injury and survival. We performed RNA sequencing of lung tissue in wild-type and IFNAR1-/- mice after LPS and bleomycin injury. Our unbiased analysis identified differentially expressed genes between IFNAR1-/- and wild-type mice, including previously unknown regulation of nucleotide-binding oligomerization domain (NOD)-like receptor signaling, retinoic acid-inducible gene-I (RIG-I) signaling, and necroptosis pathway by type I interferon signaling in both models. These data provide novel insights into the conserved anti-inflammatory mechanisms of the type I interferon signaling.NEW & NOTEWORTHY Type I interferons are known for their antiviral activities. In this study, we demonstrate a conserved anti-inflammatory role of type I interferon signaling against diverse stimuli in the lung. We show that exacerbated inflammatory response in the absence of type I interferon signaling has both acute and chronic consequences in the lung including structural changes.
摘要：
过度或持续的炎症可能对肺结构和功能产生有害影响。目前,我们对控制炎症反应的保守宿主机制的理解还不完全清楚.在这项研究中,我们研究了I型干扰素信号传导在针对不同临床相关刺激的炎症反应中的作用.使用缺乏I型干扰素信号（IFNAR1-/-）的小鼠，我们证明，干扰素信号的缺乏导致对铜绿假单胞菌的强烈和持续的炎症反应，脂多糖，和化疗药物博来霉素。IFNAR1-/-小鼠的炎症反应升高表现为巨噬细胞和中性粒细胞等骨髓细胞升高，支气管肺泡灌洗.IFNAR1-/-小鼠中的炎性细胞应答持续至14天,并且在博来霉素损伤后IFNAR1-/-小鼠中存在肺的受损恢复和纤维化重塑。在假单胞菌感染模型中,炎症细胞反应升高导致IFNAR1-/-小鼠的细菌清除率提高，虽然有相似的肺损伤和生存。我们在LPS和博来霉素损伤后对野生型和IFNAR1-/-小鼠的肺组织进行RNA测序。我们的无偏分析确定了IFNAR1-/-和野生型小鼠之间的差异表达基因，包括以前未知的NOD样受体信号的调节，RIG-I信号,两种模型中I型干扰素信号传导和坏死途径。这些数据提供了对I型干扰素信号传导的保守抗炎机制的新见解。
