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

• 批准号: 10582936
• 负责人: David Andrew Hill
• 金额: $ 60.22万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10582936
• 关键词: Address; Adipose tissue; Adopted; Adult; Asthma; Atherosclerosis; Biological Models; Bronchoalveolar Lavage; CASP1 gene; Cells; Characteristics; Childhood; Childhood Asthma; Clinical; Collaborations; Culture Techniques; Data; Deposition; Development; Event; Extrinsic asthma; Fatty Acids; Flow Cytometry; Future; Genetic; Grant; Human; Immune; Immune response; Immunologics; In Vitro; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-1 alpha; Knowledge; Lipids; Lung; Macrophage; Macrophage Activation; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Modeling; Mus; Obese Mice; Obesity; Obesity associated disease; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Population; Process; Proteins; Publishing; Pulmonary Inflammation; Reporter; Resources; Risk; Sampling; Signal Pathway; Signal Transduction; Societies; Stearates; Steatohepatitis; Stimulus; Structure of parenchyma of lung; TNF gene; Techniques; Testing; Therapeutic; Thinness; Tissues; Translating; Work; airway inflammation; immunopathology; in vivo; inflammatory lung disease; innovation; insight; lipidome; lipidomics; mouse model; neutrophil; new therapeutic target; novel; obese person; obesity-associated asthma; programs; response; stem; targeted treatment; therapeutic development; transcriptome sequencing; transcriptomics

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.

项目概要/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 这些不良的临床结果通常比特应性哮喘更严重且更难以治疗。 OAA 独特的免疫病理学，包括肺部免疫细胞对炎症反应的差异 我们对异质性但以中性粒细胞为主的肺部炎症的理解有限。 肥胖改变肺部先天免疫细胞对炎症刺激的反应，阻碍新型免疫细胞的发展 OAA 的预防和治疗方法 肥胖会导致肺部脂质沉积和脂质沉积。 这些过程可能会导致 OAA。 免疫病理学，因为 TRM 与哮喘发病机制密切相关，并且对 尽管如此，我们不知道肺 TRM 是否采用不同的方式。 肥胖导致的免疫代谢和功能程序，或者肥胖相关的肺 TRM 是否有贡献 为了开始解决这一知识差距，我们对精益肺 TRM 进行了初步研究。 我们观察到表达免疫代谢特征蛋白的载脂 TRM。 使用最小偏差脂质组学和肥胖小鼠肺部的重编程和炎症激活。 在体外培养技术中，我们已确定脂肪酸硬脂酸酯是可能影响的关键代谢信号 最后，我们发现肥胖和硬脂酸盐会激活肺TRM炎症功能。 TRM 炎性体——肥胖期间在非肺 TRM 中观察到的结果，可能有助于 基于这些数据，我认为硬脂酸盐会激活免疫代谢。 肺 TRM 中的功能程序会导致炎症小体介导的炎症反应过度 此项资助的目标是：(1) 识别脂质信号、细胞代谢途径，以及 小鼠肥胖相关肺 TRM 免疫代谢重编程的炎症后果 人类和 (2) 测试 TRM 炎症小体对 OAA 样先天性肺部炎症的贡献。 为了实现这些目标，我们开发或获得了新颖的小鼠模型系统并建立了独特的 合作将使我们能够机械地探究与肥胖相关的免疫代谢 对小鼠肺 TRM 进行重新编程，并将我们的观察结果转化为儿童和成人受试者。 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部疾病。