Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan; Japan Society for the Promotion of Science, Tokyo, Japan.
Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
Biochem Biophys Res Commun. 2019 May 28;513(2):405-411. doi: 10.1016/j.bbrc.2019.03.211. Epub 2019 Apr 6.
Increasing evidence indicates that obesity is a risk factor for increased severity of influenza virus infection. However, its precise immunological mechanism is not fully understood. To investigate this, diet-induced obese (DIO) mice were established by feeding C57BL/6 male mice a high-fat diet for 16 weeks. DIO and lean control mice were infected intranasally with 3000 pfu of influenza A virus (IAV) (PR8/H1N1). Interestingly, we found adipose tissue located along the bronchus in naïve DIO mice. In addition, the Nos2 level was significantly higher and Arg1 level was significantly lower in lung macrophages of naïve DIO mice, consistent with an M1-skewed phenotype. The survival rate and body weight of DIO mice infected with IAV were significantly lower than those of lean control mice and associated with higher viral load in the lungs of DIO mice. Histopathological analysis demonstrated higher numbers of inflammatory cells in the lungs of DIO mice after IAV infection. Levels of cytokines, including TNF-α, IL-6, IL-10, and type I IFN (IFN-α and IFN-β), in bronchoalveolar lavage fluid (BALF) were altered after IAV infection; in particular, IFN-α and IFN-β levels were significantly suppressed in the BALF of DIO mice. In vitro, bone marrow-derived macrophages were stimulated with ligands of toll-like receptor (TLR) 7/8, a pattern recognition receptor for single-stranded RNA, and levels of TNF-α, IL-6, and IL-10 were similarly altered. In addition, levels of IFN-α and IFN-β were significantly lower in culture supernatants of alveolar macrophages sorted from naïve DIO mice and infected with IAV, compared to those in macrophages sorted from lean control mice. Collectively, these results suggest that macrophages may be the main contributors to poor outcomes of influenza virus infection in obesity.
越来越多的证据表明，肥胖是流感病毒感染加重的一个危险因素。然而，其确切的免疫学机制尚不完全清楚。为了研究这一点，通过给 C57BL/6 雄性小鼠喂食高脂肪饮食 16 周来建立饮食诱导肥胖（DIO）小鼠。DIO 和瘦对照组小鼠经鼻腔感染 3000 噬菌斑形成单位（pfu）的流感 A 病毒（IAV）（PR8/H1N1）。有趣的是，我们在未感染的 DIO 小鼠的支气管旁发现了脂肪组织。此外，与瘦对照组相比，未感染的 DIO 小鼠肺巨噬细胞中的 Nos2 水平显著升高，Arg1 水平显著降低，这与 M1 表型偏倚一致。感染 IAV 的 DIO 小鼠的存活率和体重明显低于瘦对照组小鼠，并且 DIO 小鼠肺部的病毒载量更高。组织病理学分析表明，IAV 感染后 DIO 小鼠肺部的炎症细胞数量更多。感染 IAV 后，支气管肺泡灌洗液（BALF）中的细胞因子水平，包括 TNF-α、IL-6、IL-10 和 I 型 IFN（IFN-α 和 IFN-β）发生改变；特别是，DIO 小鼠 BALF 中的 IFN-α 和 IFN-β 水平显著受到抑制。在体外，用单链 RNA 的模式识别受体 Toll 样受体（TLR）7/8 的配体刺激骨髓来源的巨噬细胞，TNF-α、IL-6 和 IL-10 的水平也发生了类似的改变。此外，与从瘦对照组小鼠分离的肺泡巨噬细胞相比，从未感染的 DIO 小鼠分离并感染 IAV 的肺泡巨噬细胞的培养上清液中 IFN-α 和 IFN-β 的水平显著降低。总之，这些结果表明，巨噬细胞可能是肥胖流感病毒感染不良结局的主要贡献者。
