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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要囊性纤维化 (CF) 患者患有慢性感染和肺部炎症，导致支气管扩张最终导致呼吸衰竭。尽管最近取得了进展，包括批准高效的 CFTR 调节剂疗法 (HEMT) 改善了 CF (PwCF)、慢性感染和炎症是发病的主要原因。尽管炎症的严重程度已知 CF 肺中的反应增加，持续炎症的机制是未知。我们已经证明，肺巨噬细胞对于 CF 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，以及招募到肺的肺巨噬细胞对炎症刺激作出反应。我们的初步数据表明 CF 招募了肺巨噬细胞与其他人相比，Nrf2 的表达减少，Nrf2 是一种已知调节细胞代谢的转录因子非 CF 支气管扩张和对照受试者相比，HEMT 并没有改善这一情况。我们还发现CF 即使在 HEMT 的情况下，招募的肺巨噬细胞也持续糖酵解和炎症，而非 CF 支气管扩张和健康招募的肺巨噬细胞可以转变为炎症消退表型。由于免疫细胞串扰可以由细胞外囊泡（EV）介导，我们研究了常驻肺巨噬细胞 EV 对招募的肺巨噬细胞炎症反应的影响发现 CF 常驻肺巨噬细胞 EV 在招募的肺巨噬细胞中诱导持续炎症。最后，我们的初步数据显示，预计抑制 Nrf2 的 miRNA 增加，并且 miRNA 水平降低。解决 CF 驻留肺巨噬细胞 EV 中的脂质炎症。因此，我们假设特定 CF 驻留 LM EV 中的 miRNA 和脂质会降低招募的 LM 中的 Nrf2 水平，从而导致持久的糖酵解和未能转变为炎症消退表型。在目标 1 中，我们将检验假设 CF 肺巨噬细胞存在功能上重要的免疫代谢差异，这些差异是特定于 CF 并在 HEMT 后持续存在。在这个目标中，我们将全面描述肺巨噬细胞亚群的特征 CF 肺并将量化居民和患者之间细胞代谢和炎症消退的差异在 PwCF、非 CF 支气管扩张受试者和健康受试者中招募肺巨噬细胞。在目标 2 中，我们将检验以下假设：CF 常驻肺巨噬细胞释放的 EV 内的特定 miRNA 会影响募集的肺巨噬细胞的炎症反应。在目标 3 中，我们将检验脂质的假设 CF 驻留肺巨噬细胞释放的 EV 含量可防止炎症消退的转变募集的肺巨噬细胞的表型。拟议的研究是独一无二的，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 持续性肺部炎症机制的新的重要信息，并将让我们能够确定新疗法的目标，以减少有害的 CF 肺部炎症并改善生活 CF 患者的寿命和寿命。