The Role of Macrophage Metabolic Crosstalk in CF Chronic Lung Inflammation

巨噬细胞代谢串扰在 CF 慢性肺部炎症中的作用

• 批准号: 10930185
• 负责人: ALIX ASHARE
• 金额: $ 63.73万
• 依托单位: DARTMOUTH-HITCHCOCK CLINIC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10930185
• 关键词: Binding; Bronchiectasis; Cells; Chronic; Clinical Medicine; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Failure; Glycolysis; Goals; Immune; Impairment; Inflammation; Inflammatory; Inflammatory Response; Investigation; Ion Channel; Knowledge; Lipids; Longevity; Lung; Lung infections; Macrophage; Mediating; Metabolic; Metabolism; MicroRNAs; Mission; Morbidity - disease rate; Mutation; Pathogenesis; Pathway interactions; Persons; Phenotype; Population; Public Health; Pulmonary Cystic Fibrosis; Pulmonary Inflammation; Quality of life; Regulator Genes; Research; Resolution; Respiratory Failure; Role; Sampling; Stimulus; Surface; Testing; Transfection; United States National Institutes of Health; cell type; chronic infection; cohort; cystic fibrosis patients; differential expression; extracellular vesicles; human disease; human subject; improved; innovation; neutrophil; new therapeutic target; novel therapeutic intervention; prevent; recruit; response; transcription factor; translational study; vesicular release

Project Summary Patients with cystic fibrosis (CF) suffer from chronic infections and lung inflammation leading to bronchiectasis and, ultimately, respiratory failure. Although recent advances, including the approval of highly effective CFTR modulator therapy (HEMT), have improved the overall quality of life of people with CF (PwCF), chronic infection and inflammation are the primary cause of morbidity. Although the magnitude of the inflammatory response is known to be increased in the CF lung, the mechanisms underlying persistent inflammation are unknown. We have shown that lung macrophages are critical to the local inflammatory response in CF. Lung macrophages include resident lung macrophages, as well as lung macrophages that are recruited to the lung in response to inflammatory stimuli. Our preliminary data demonstrate that CF recruited lung macrophages have decreased expression of Nrf2, a transcription factor known to regulate cellular metabolism, compared to non-CF bronchiectasis and control subjects, and this did not improve with HEMT. We also found that CF recruited lung macrophages are persistently glycolytic and inflammatory, even in the setting of HEMT, while non-CF bronchiectasis and healthy recruited lung macrophages can transition to an inflammation resolving phenotype. As immune cell crosstalk can be mediated by extracellular vesicles (EVs), we investigated the impact of resident lung macrophage EVs on the inflammatory response of recruited lung macrophages and found that CF resident lung macrophage EVs induce persistent inflammation in recruited lung macrophages. Lastly, we have preliminary data showing increased miRNAs predicted to inhibit Nrf2 and reduced levels of inflammation resolving lipids in EVs from CF resident lung macrophages. Thus, we hypothesize that specific miRNAs and lipids within CF resident LM EVs reduce Nrf2 levels in recruited LMs, causing persistent glycolysis and failure to transition to an inflammation resolving phenotype. In Aim 1, we will test the hypothesis that there are functionally important immunometabolic differences in CF lung macrophages that are specific to CF and persist after HEMT. In this Aim, we will fully characterize subpopulations of lung macrophages in the CF lung and will quantify differences in cellular metabolism and inflammation resolution between resident and recruited lung macrophages in PwCF, non-CF bronchiectasis subjects, and healthy subjects. In Aim 2, we will test the hypothesis that specific miRNAs within EVs released by CF resident lung macrophages impact the inflammatory response of recruited lung macrophages. In Aim 3, we will test the hypothesis that the lipid content of EVs released by CF resident lung macrophages prevents the shift to an inflammation resolution phenotype in recruited lung macrophages. The proposed studies are unique because they involve human subjects before and after HEMT and thus, our data will be directly relevant to PwCF. In addition, our studies will provide new and essential information on the mechanisms of persistent lung inflammation in CF and will allow us to identify targets for novel therapies to reduce harmful CF lung inflammation and improve the lives and longevity of people living with CF.

项目摘要 囊性纤维化患者（CF）患有慢性感染和肺部炎症，导致支气管扩张 最终，呼吸衰竭。尽管最近的进步，包括批准高效CFTR 调节剂治疗（HEMT），改善了CF（PWCF），慢性的人的整体生活质量 感染和炎症是发病率的主要原因。虽然炎症的大小 已知反应在CF肺中增加，持续炎症的机制是 未知。我们已经表明，肺巨噬细胞对于CF中的局部炎症反应至关重要。肺 巨噬细胞包括常驻肺巨噬细胞，以及募集到肺的肺巨噬细胞 响应炎症刺激。我们的初步数据表明，CF招募了肺巨噬细胞 NRF2的表达降低，NRF2是一种已知调节细胞代谢的转录因子，与 非CF支气管扩张和对照受试者，这与HEMT没有改善。我们还发现CF 招募的肺巨噬细胞持续糖酵解和炎症性，即使在Hemt的情况下， 非CF支气管扩张和健康招募的肺巨噬细胞可以过渡到炎症。 表型。由于可以通过细胞外囊泡（EV）介导免疫细胞串扰，因此我们研究了 居民肺巨噬细胞电动汽车对招募肺巨噬细胞炎症反应的影响 发现CF常驻肺巨噬细胞EV会在招募的肺巨噬细胞中引起持续的炎症。 最后，我们的初步数据显示，预测的miRNA抑制NRF2和降低水平。 CF常驻肺巨噬细胞中电动汽车中的脂质解决脂质。因此，我们假设该特定 CF居民LM EV中的miRNA和脂质降低了招募LMS的NRF2水平，从而导致持久 糖酵解和未能过渡到炎症解决表型。在AIM 1中，我们将检验假设 在CF肺巨噬细胞中有功能上重要的免疫代谢差异 CF并在下摆后持续。在此目标中，我们将充分表征肺巨噬细胞的亚群 CF肺并将量化居民和居民之间的细胞代谢和炎症的差异 在普华永道，非CF支气管扩张受试者和健康受试者中招募的肺巨噬细胞。在AIM 2中，我们将 检验以下假设：CF居民肺巨噬细胞释放的电动汽车中的特定miRNA影响 招募的肺巨噬细胞的炎症反应。在AIM 3中，我们将测试脂质的假设 CF居民肺巨噬细胞发布的电动汽车含量可防止转向炎症分辨率 招募的肺巨噬细胞中的表型。拟议的研究是独特的，因为它们涉及人类 HEMT之前和之后的受试者，因此，我们的数据将与PWCF直接相关。此外，我们的研究 将提供有关CF中持续性肺部炎症机制的新的基本信息，并将 允许我们确定新型疗法的靶标，以减少有害的CF肺部炎症并改善生命 和居住在CF的人的寿命。