Impact of Obesity on Lung Macrophage Metabolism and Inflammation

项目摘要/摘要 肥胖会增加儿童和成人患哮喘的风险，而肥胖相关哮喘(OAA)是 通常比特应性哮喘更严重、更难治疗。这些不良的临床结果可能源于 OAA独特的免疫病理学，包括肺免疫细胞对炎症反应的不同 刺激和异质性但以中性粒细胞为主的肺部炎症。我们有限的理解是如何 肥胖改变肺固有免疫细胞对炎症刺激的反应阻碍新的发展 高龄津贴的预防和治疗方法。肥胖导致肺内脂肪沉积和脂肪 肺组织内滞留巨噬细胞(TRMS)的蓄积。这些过程可能会导致高龄津贴 免疫病理学如TRMS既与哮喘发病密切相关，又对 肥胖时的免疫代谢重编程。尽管如此，我们不知道肺TRMS是否采用了不同的 肥胖导致的免疫代谢和功能程序，或肥胖相关的肺TRMS是否有贡献 致高龄津贴。为了开始解决这一知识差距，我们对LEAN患者的肺TRMS进行了初步研究 还有肥胖的老鼠。我们观察到载脂的TRMS表达具有免疫代谢特征的蛋白质。 肥胖小鼠肺部的重编程和炎症激活。使用最小偏向的脂质组学和 在体外培养技术中，我们已经确定硬脂酸是一个关键的代谢信号，可能会影响 肥胖时肺TRM的炎症功能。最后，我们发现肥胖和硬脂酸盐会激活 TRM炎症小体--肥胖期间在非肺性TRMS中观察到的一种结果，可能有助于 OAA免疫病理学。根据这些数据，我假设硬脂酸盐激活了一种免疫代谢 肺TRMS中的功能程序导致过度炎症小体介导的炎症反应 天生的刺激。这笔赠款的目的是：(1)确定脂质信号、细胞代谢途径和 肥胖相关肺TRM免疫代谢重编程对小鼠炎症反应的影响 和(2)测试TRM炎症体对OAA样先天肺部炎症的贡献。要达到 这些目标，我们开发或获得了新颖的小鼠模型系统，并建立了独一无二的 合作将允许我们机械地审问与肥胖相关的免疫代谢 对小鼠的肺TRMS进行重新编程，并将我们的观察结果转化为儿科和成人受试者。这样做的话 将确定未来OAA特定疗法可以针对的分子和途径，并为研究提供信息 其他与肥胖相关的炎症性肺部疾病。

PROJECT SUMMARY/ABSTRACT Obesity increases the risk of developing asthma in children and adults, and obesity-associated asthma (OAA) is often more severe and more difficult to treat than atopic asthma. These poor clinical outcomes may stem from OAA’s distinct immunopathology that includes differences in how lung immune cells respond to inflammatory stimuli and a heterogeneous but neutrophil-predominant lung inflammation. Our limited understanding of how obesity alters lung innate immune cell responses to inflammatory stimuli hinders the development of novel preventative and therapeutic approaches for OAA. Obesity causes lipid deposition in the lung and lipid accumulation in lung tissue resident macrophages (TRMs). These processes may contribute to OAA immunopathology as TRMs are both intimately involved in asthma pathogenesis and sensitive to immunometabolic reprogramming during obesity. Despite this, we do not know if lung TRMs adopt distinct immunometabolic and functional programs as a result of obesity, or if obesity-associated lung TRMs contribute to OAA. To begin to address this knowledge gap, we have performed preliminary studies of lung TRMs in lean and obese mice. We observe lipid-laden TRMs that express proteins characteristic of immunometabolic reprogramming and inflammatory activation in the lungs of obese mice. Using minimally biased lipidomics and in vitro culture techniques, we have identified the fatty acid stearate as a key metabolic signal that may influence lung TRM inflammatory functions during obesity. Finally, we find that obesity and stearate cause activation of the TRM inflammasome—an outcome that is observed in non-lung TRMs during obesity and may contribute to OAA immunopathology. Based on these data, I hypothesize that stearate activates an immunometabolic functional program in lung TRMs that causes exaggerated inflammasome-mediated inflammation in response to innate stimuli. The objectives of this grant are to: (1) identify the lipid signals, cellular metabolic pathways, and inflammatory consequences of obesity-associated lung TRM immunometabolic reprogramming in mice and humans and (2) test the contribution of the TRM inflammasome to OAA-like innate lung inflammation. To attain these objectives, we have developed or obtained novel mouse model systems and established unique collaborations that will allow us to mechanistically interrogate obesity-associated immunometabolic reprogramming of lung TRMs in mice, and translate our observations to pediatric and adult subjects. Doing so will identify molecules and pathways that can be targeted by future OAA-specific therapeutics, and inform studies of other obesity-associated inflammatory lung diseases.