Hif-1 alpha metabolically reprograms recruited alveolar macrophages to promote lung repair

Hif-1 α 通过代谢重新编程招募的肺泡巨噬细胞以促进肺修复

• 批准号: 9309186
• 负责人: William Janssen
• 金额: $ 54.99万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2018-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9309186
• 关键词: Acute; Acute Lung Injury; Address; Affect; Alveolar; Alveolar Cell; Alveolar Macrophages; Alveolus; Apoptosis; Blood capillaries; Capillary Endothelial Cell; Cell Proliferation; Cells; Cessation of life; Complex; Data; Defect; Embryonic Development; Endothelial Cells; Endothelium; Energy Metabolism; Epithelial; Epithelial Cells; Functional disorder; Gases; Genes; Genetic Transcription; Glycolysis; HIF1A gene; Health; Histologic; Homeostasis; Hypoxia Inducible Factor; Impairment; Inflammation; Injury; Life; Lung; Metabolic; Metabolism; Molecular; Mus; Oxidative Phosphorylation; Pathologic; Pathway Analysis; Platelet-Derived Growth Factor; Play; Pneumonia; Process; Production; Proliferating; Recovery; Recruitment Activity; Respiratory physiology; Role; Site; Stable Populations; Structure; Testing; Therapeutic Intervention; Time; Tissues; Vascular Endothelial Growth Factors; Warburg Effect; Wild Type Mouse; aerobic glycolysis; alveolar epithelium; anaerobic glycolysis; capillary; cell injury; differential expression; functional restoration; inflammatory lung disease; injured; lung injury; lung repair; macrophage; meetings; migration; monocyte; neutrophil; programs; repaired; response to injury; restoration; self-renewal; tissue repair; tool; transcriptome sequencing

PROJECT SUMMARY Pneumonia and acute inflammatory diseases of the lungs affect over 450 million people worldwide each year and result in over 4 million deaths. Pathologic hallmarks include neutrophil accumulation in the airspaces, injury to alveolar epithelial and endothelial cells, and resultant loss of epithelial-capillary integrity with impaired gas exchange. Accordingly, restoration of lung function requires repair of injured alveoli, replacement of injured epithelial and endothelial cells, and re-establishment of capillary barrier function. Macrophages are recognized as critical orchestrators of tissue repair, however the mechanisms that drive their programming are poorly understood. During health the airspaces are occupied by a stable population of resident alveolar macrophages (RAM) that arise during embryogenesis and self-renew throughout life. RAMs remain during inflammation but are joined by recruited macrophages (RecMΦ) that arise from circulating monocytes. These RecMΦ remain in the lung while lung structure and function are restored, and then undergo apoptosis leaving RAMs to once again populate the healthy airspaces. The contributions provided by RAM and RecMΦ to alveolar repair are largely unknown and represent an important barrier to advancement in the field. In order to address this unmet need, our group performed time-resolved RNA sequencing on RAMs and RecMΦ isolated from LPS treated mice during acute and resolving inflammation. Our data showed marked differences in the transcriptomal profiles of RAMs and RecMΦ at all time points studied, with over 50% of genes differentially expressed. Pathway analysis and functional studies demonstrated that RecMΦ produce high levels of epithelial and endothelial proliferative factors and suggested that RecMΦ are key orchestrators of tissue repair. Studies using CCR2 -/- mice, which have defects in monocyte migration and impaired accumulation of RecMΦ, further supported this concept; LPS treated CCR2-/- and wild type mice had equivalent degrees of lung injury, but CCR2-/- mice had reduced epithelial and endothelial proliferation and prolonged capillary barrier dysfunction. Transcriptomal and metabolic analyses suggested that HIF-1α transcription and stabilization were increased in RecMΦ and that HIF-1α induced metabolically reprograming the RecMΦ toward glycolysis. These data led us to hypothesize that RecMΦ are essential orchestrators of epithelial and endothelial cell proliferation following acute lung injury and that the relevant programming of RecMΦ is driven by HIF-1α and glycolytic energy metabolism. This will be tested in three Specific Aims. 1) Test the hypothesis that recruited macrophages are programed to stimulate proliferation of alveolar epithelial and endothelial cells following acute lung injury. 2) Test the hypothesis that glycolytic metabolism in recruited macrophages promotes their production of epithelial and endothelial proliferative factors and stimulates tissue repair. 3) Test the hypothesis that HIF-1α is responsible for metabolic reprogramming of recruited macrophages with enhanced anaerobic glycolysis and reduced oxidative phosphorylation.

项目摘要 肺炎和肺部急性炎症性疾病每年影响全球超过4.5亿人 导致超过四百万人死亡病理学特征包括中性粒细胞聚集在空气中， 肺泡上皮细胞和内皮细胞损伤，导致上皮-毛细血管完整性丧失， 气体交换因此，肺功能的恢复需要修复受损的肺泡，替换受损的肺泡。 上皮和内皮细胞，以及毛细血管屏障功能的重建。巨噬细胞被识别 作为组织修复的关键管弦乐队，然而，驱动其编程的机制很差， 明白在健康期间，空气空间被稳定的肺泡巨噬细胞群体占据 (RAM)在胚胎发育过程中产生并在整个生命过程中自我更新。RAM在炎症期间仍然存在， 通过从循环单核细胞产生的募集的巨噬细胞（RecMΦ）加入。这些RecMΦ保持在 而肺的结构和功能得到恢复，然后经历细胞凋亡，留下RAMs一次 再次填充健康的空气空间。RAM和RecMΦ对牙槽修复的贡献是 大部分是未知的，并且是该领域进步的重要障碍。为了解决这一未满足的问题， 根据需要，我们的小组对从LPS处理的小鼠中分离的RAM和RecMΦ进行了时间分辨RNA测序。 小鼠在急性和缓解炎症。我们的数据显示，在转录组中， 在研究的所有时间点的RAM和RecMΦ的谱中，超过50%的基因差异表达。 通路分析和功能研究表明，RecMΦ产生高水平的上皮和 提示RecMΦ是组织修复的关键环节。研究 使用具有单核细胞迁移缺陷和RecMΦ积累受损的CCR 2-/-小鼠，进一步 LPS处理的CCR 2-/-和野生型小鼠具有同等程度的肺损伤，但 CCR 2-/-小鼠上皮和内皮细胞增殖减少，毛细血管屏障功能障碍延长。 转录组和代谢分析表明，HIF-1α的转录和稳定性增加， RecMΦ和HIF-1α诱导RecMΦ向糖酵解代谢重编程。这些数据让我们 假设RecMΦ是上皮细胞和内皮细胞增殖的重要协调， RecMΦ的相关编程由HIF-1α和糖酵解能量驱动 新陈代谢.这将在三个具体目标中得到检验。1)测试募集的巨噬细胞是 编程以刺激急性肺损伤后肺泡上皮细胞和内皮细胞的增殖。（二） 检验募集的巨噬细胞中糖酵解代谢促进其上皮细胞生成的假设。 和内皮增殖因子并刺激组织修复。3)验证HIF-1α是 负责募集的巨噬细胞的代谢重编程，增强无氧糖酵解， 减少氧化磷酸化。

项目成果

Kinetics of the angiogenic response in lung endothelium following acute inflammatory injury with bleomycin.

• DOI: 10.3109/01902148.2014.938202
• 发表时间: 2014-10
• 期刊: Experimental lung research
• 影响因子: 1.7
• 作者: Yunt ZX;Mohning MP;Barthel L;Kearns MT;Tuder RM;Hyde DM;Henson PM;Janssen WJ
• 通讯作者: Janssen WJ

Defective efferocytosis by alveolar macrophages in IPF patients.

• DOI: 10.1016/j.rmed.2012.08.020
• 发表时间: 2012-12
• 期刊: RESPIRATORY MEDICINE
• 影响因子: 4.3
• 作者: Morimoto, Konosuke;Janssen, William J.;Terada, Mayumi
• 通讯作者: Terada, Mayumi

Neutrophil-mediated T-Cell Suppression in Influenza: Novel Finding Raising Additional Questions.

流感中中性粒细胞介导的 T 细胞抑制：新发现引发了更多问题。

• DOI: 10.1165/rcmb.2017-0425ed
• 发表时间: 2018
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4
• 作者: Zemans,RachelL

Lung disease in rheumatoid arthritis.

• DOI: 10.1016/j.rdc.2014.12.004
• 发表时间: 2015-05
• 期刊: RHEUMATIC DISEASE CLINICS OF NORTH AMERICA
• 影响因子: 2.3
• 作者: Yunt, Zulma X.;Solomon, Joshua J.
• 通讯作者: Solomon, Joshua J.

Selective and inducible targeting of CD11b+ mononuclear phagocytes in the murine lung with hCD68-rtTA transgenic systems.

使用 hCD68-rtTA 转基因系统选择性和诱导性靶向小鼠肺中的 CD11b 单核吞噬细胞。

• DOI: 10.1152/ajplung.00141.2016
• 发表时间: 2016
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: McCubbrey,AlexandraL;Barthel,Lea;Mould,KaraJ;Mohning,MichaelP;Redente,ElizabethF;Janssen,WilliamJ
• 通讯作者: Janssen,WilliamJ