Impact of Obesity on Lung Macrophage Metabolism and Inflammation

肥胖对肺巨噬细胞代谢和炎症的影响

基本信息

  • 批准号:
    10582936
  • 负责人:
  • 金额:
    $ 60.22万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-12-15 至 2027-11-30
  • 项目状态:
    未结题

项目摘要

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.
项目总结/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且更难治疗。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差异, 刺激和异质性但嗜中性粒细胞为主的肺部炎症。我们对人类 肥胖改变了肺固有免疫细胞对炎症刺激的反应, OAA的预防和治疗方法。肥胖会导致肺部脂质沉积, 在肺组织驻留巨噬细胞(TRM)中蓄积。这些过程可能有助于高龄津贴 作为TRM的免疫病理学与哮喘发病机制密切相关, 肥胖期间的免疫代谢重编程。尽管如此,我们不知道肺TRM是否采用不同的 免疫代谢和功能程序作为肥胖的结果,或者如果肥胖相关的肺TRM有助于 到OAA。为了开始解决这一知识空白,我们对瘦猪的肺TRM进行了初步研究, 和肥胖小鼠。我们观察到富含脂质的TRM表达免疫代谢特征蛋白, 在肥胖小鼠的肺部重编程和炎症激活。使用最小偏差的脂质组学, 在体外培养技术中,我们已经确定脂肪酸硬脂酸酯作为一个关键的代谢信号,可能会影响 肥胖期间肺TRM炎症功能。最后,我们发现肥胖和硬脂酸盐会激活 TRM炎性小体-肥胖期间在非肺TRM中观察到的结果, OAA免疫病理学基于这些数据,我假设硬脂酸盐激活了免疫代谢 肺TRM中的功能程序,其引起对以下反应的过度炎性小体介导的炎症 先天刺激该基金的目标是:(1)确定脂质信号,细胞代谢途径, 小鼠中肥胖相关肺TRM免疫代谢重编程的炎症后果, 人和(2)测试TRM炎性体对OAA样先天性肺部炎症的贡献。实现 这些目标,我们已经开发或获得了新的小鼠模型系统,并建立了独特的 合作,这将使我们能够机械地询问肥胖相关的免疫代谢 在小鼠中重新编程肺TRM,并将我们的观察转化为儿科和成人受试者。这样做 将确定未来OAA特异性疗法可以靶向的分子和途径,并为研究提供信息。 其他与肥胖相关的炎症性肺病。

项目成果

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David Andrew Hill其他文献

David Andrew Hill的其他文献

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{{ truncateString('David Andrew Hill', 18)}}的其他基金

Role of miR-6236 in Obesity-Associated Adipose Tissue Dysfunction
miR-6236 在肥胖相关脂肪组织功能障碍中的作用
  • 批准号:
    10441535
  • 财政年份:
    2021
  • 资助金额:
    $ 60.22万
  • 项目类别:
Role of miR-6236 in Obesity-Associated Adipose Tissue Dysfunction
miR-6236 在肥胖相关脂肪组织功能障碍中的作用
  • 批准号:
    10282575
  • 财政年份:
    2021
  • 资助金额:
    $ 60.22万
  • 项目类别:
The role of unique adipose tissue macrophage populations in obesity
独特的脂肪组织巨噬细胞群在肥胖中的作用
  • 批准号:
    10393527
  • 财政年份:
    2018
  • 资助金额:
    $ 60.22万
  • 项目类别:
The role of unique adipose tissue macrophage populations in obesity
独特的脂肪组织巨噬细胞群在肥胖中的作用
  • 批准号:
    9910385
  • 财政年份:
    2018
  • 资助金额:
    $ 60.22万
  • 项目类别:

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