Adipose Tissue Inflammation in Influenza Infection Severity

摘要 肥胖症的流行有增无减，困扰着全世界超过5亿人。流行病学证据 确定肥胖是流感感染易感性和严重程度增加的独立危险因素。 改变的免疫细胞功能（例如细胞因子产生）通常被认为是增加免疫缺陷的关键致病因素。 肺组织损伤然而，脂肪细胞的贡献，在肥胖症中占主导地位的改变的细胞类型， 免疫样特性，流感发病机制仍然在很大程度上被忽视。值得注意的是，肥胖促进脂肪细胞 倾向于促炎状态并放大它们的免疫样作用。在此，我们建议 检查脂肪细胞炎症能力对流感疾病发病机制的贡献。我们的新型 初步数据强烈提示流感诱导的I型干扰素（IFN）敏感性偏离脂肪细胞特异性 炎症能力，并促进与不成比例的肺相关的全身和组织炎症 组织损伤。我们的初步研究结果表明：与感染流感的肥胖小鼠相比， 瘦对照显示：（a）死亡率增加;（B）肺组织病理学更严重;（c）肺水肿增加; 和（d）升高的肺IL-6水平。此外，我们表明，流感感染：（e）直接形状的白色脂肪 组织（WAT）免疫细胞浸润并增加WAT I型IFN/IFNAR轴活化;和（f）诱导 脂肪细胞IL-6炎症反应。最后，我们表明：（g）肥胖放大脂肪细胞炎症活力 通过I型IFN/IFNAR轴;（h）脂肪细胞有助于全身性炎性细胞因子产生;和（i） 脂肪细胞分泌的因子加重肺上皮细胞炎症。我们的数据和现有文献支持 一种新的假设，IFNAR依赖性激活脂肪细胞炎症能力促进 脂肪细胞IL-6的产生，并放大流感感染驱动的肺部疾病的严重性肥胖。我们 我建议通过以下方法来检验这一假设：（i）确定流感感染对脂肪细胞炎症的影响 容量和肺组织损伤的肥胖症（目的1）;（ii）确定的贡献，脂肪细胞为中心的IL-6 在肥胖症中流感相关组织损伤的产生（目的2）。我们的学习将增进 脂肪细胞驱动的炎症活力和这种炎症对人类疾病的影响。考虑 全球肥胖人群的趋势，确定了这些细胞炎症过程的贡献 将为发现新的治疗靶点提供一个强大的平台，以减少流感的临床负担。

ABSTRACT The obesity pandemic continues unabated, afflicting >500 million people worldwide. Epidemiological evidence establishes obesity as an independent risk factor for increased susceptibility and severity to Influenza infection. Altered immune cell function (e.g. cytokine production) is often perceived as a key causative factor for increased lung tissue damage. However, the contribution of adipocytes, the dominantly altered cell type in obesity with immune-like properties, to Influenza pathogenesis remains largely ignored. Notably, obesity promotes adipocyte skewing towards a proinflammatory state and amplifies their immune-like contribution. Here we propose to examine the contribution of adipocyte inflammatory capacity to influenza disease pathogenesis. Our novel preliminary data strongly suggest that influenza-induced type I interferon (IFN) sensing skews adipocyte-specific inflammatory capacity, and promotes systemic and tissue inflammation that correlates with disproportionate lung tissue damage in mice. Our preliminary findings indicate that: Obese mice infected with influenza, compared to lean controls, exhibit: (a) increased mortality; (b) more severe lung tissue pathology; (c) increased lung edema; and (d) elevated lung IL-6 levels. Further, we show that influenza infection: (e) directly shapes white adipose tissue (WAT) immune cell infiltration and increases WAT type I IFN/IFNAR axis activation; and (f) induces adipocyte IL-6 inflammatory responses. Lastly, we show that: (g) obesity amplifies adipocyte inflammatory vigor via the type I IFN/IFNAR axis; (h) adipocytes contribute to systemic inflammatory cytokine production; and (i) adipocyte-secreted factors exacerbate lung epithelial cell inflammation. Our data and existing literature support a novel hypothesis that IFNAR-dependent activation of adipocyte inflammatory capacity promotes adipocyte IL-6 production and amplifies influenza infection-driven lung disease severity in obesity. We propose to test this hypothesis by: (i) determining the impact of Influenza infection on adipocyte inflammatory capacity and lung tissue damage in obesity (Aim 1); (ii) determining the contribution of adipocyte-centric IL-6 production on Influenza-associated tissue damage in obesity (Aim 2). Our studies will enhance the knowledge of adipocyte-driven inflammatory vigor and the impact of such inflammation on human disease. Considering the global trend towards a more obese population, defining the contribution of these cellular inflammatory processes will provide a robust platform for discovery of novel therapeutic targets to reduce the clinical burden of influenza.