Obesity worsens the outcome of influenza virus infection associated with impaired type I interferon induction in mice
Obesity worsens the outcome of influenza virus infection associated with impaired type I interferon induction in mice
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DOI：
10.1016/j.bbrc.2019.03.211
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发表时间：
2019-05-28
影响因子：
3.1
通讯作者：
Betsuyaku, Tomoko
中科院分区：
文献类型：
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作者：
Namkoong, Ho;Ishii, Makoto;Betsuyaku, Tomoko
越来越多的证据表明，肥胖是流感病毒感染严重程度增加的危险因素。然而，其精确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 和瘦对照小鼠鼻内感染 3000 pfu 甲型流感病毒 (IAV) (PR8/H1N1)。有趣的是，我们发现脂肪组织位于幼稚 DIO 小鼠的支气管上。此外，在幼稚 DIO 小鼠的肺巨噬细胞中，Nos2 水平显着升高，Arg1 水平显着降低，这与 M1 偏向表型一致。感染IAV的DIO小鼠的存活率和体重显着低于瘦对照小鼠，并且与DIO小鼠肺部较高的病毒载量相关。组织病理学分析表明，IAV 感染后 DIO 小鼠肺部炎症细胞数量增多。 IAV感染后，支气管肺泡灌洗液（BALF）中的细胞因子，包括TNF-α、IL-6、IL-10和I型干扰素（IFN-α和IFN-β）水平发生改变；特别是，DIO小鼠BALF中的IFN-α和IFN-β水平显着受到抑制。在体外，用Toll样受体（TLR）7/8的配体刺激骨髓源性巨噬细胞，此外，与瘦对照小鼠的巨噬细胞相比，感染 IAV 的幼稚 DIO 小鼠的肺泡巨噬细胞的培养物上清液中 IFN-α 和 IFN-β 的水平也发生了类似的改变（C）。 2019 爱思唯尔公司。保留所有权利。
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 naive DIO mice. In addition, the Nos2 level was significantly higher and Arg1 level was significantly lower in lung macrophages of naive 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-alpha, IL-6, IL-10, and type I IFN (IFN-alpha and IFN-beta, in bronchoalveolar lavage fluid (BALF) were altered after IAV infection; in particular, IFN-alpha and IFN-beta 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-alpha, IL-6, and IL-10 were similarly altered. In addition, levels of IFN-alpha and IFN-beta were significantly lower in culture supernatants of alveolar macrophages sorted from naive 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. (C) 2019 Elsevier Inc. All rights reserved.