Innate immune regulation of lung inflammation through mitochondrial dynamics

通过线粒体动力学调节肺部炎症的先天免疫

• 批准号: 10659953
• 负责人: Laurel Anne Monticelli
• 金额: $ 80.95万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-02 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659953
• 关键词: Activities of Daily Living; Adoptive Transfer; Affect; Age; Allergens; Asthma; Automobile Driving; Biochemical; Bioenergetics; Catabolism; Cell physiology; Cells; Cellular biology; Cessation of life; Chemicals; Child; Clinical; Cytokine Signaling; Data; Development; Disease; Economics; Effector Cell; Exposure to; Flow Cytometry; Generations; Glucose; Glycolysis; Human; Imaging Techniques; Immune; Immunobiology; Impairment; Individual; Inflammation; Inflammatory; Knockout Mice; Knowledge; Link; Lung; Lymphoid Cell; Metabolic; Metabolism; Mitochondria; Molecular; Morphology; Mus; Nutrient; Papain; Pathologic; Pathway interactions; Peptide Hydrolases; Physicians; Pilot Projects; Population; Production; Public Health; Pulmonary Inflammation; Role; Scientist; Signal Transduction; Source; Structure of parenchyma of lung; Techniques; Testing; Therapeutic; Tissues; airway inflammation; allergic airway inflammation; asthmatic; asthmatic patient; chronic inflammatory lung disease; conditional knockout; cytokine; glucose metabolism; glucose uptake; immunoregulation; improved; inflammatory lung disease; liquid chromatography mass spectrometry; live cell imaging; lung development; mitochondrial fitness; mitochondrial membrane; mouse model; novel; prevent; response; restraint; transcriptome sequencing

PROJECT SUMMARY In the US alone, asthma affects approximately 24 million individuals, 6 million of whom are children under the age of 18, and is responsible for over 3,000 deaths annually1,2. A population of immune cells, called group 2 innate lymphoid cells (ILC2s), are integral in driving lung inflammatory diseases including asthma through production of type 2 cytokines in response to tissue `alarmin' cytokine signals. Despite these advances on ILC2 function, there is a fundamental gap in our knowledge of the intracellular pathways that control this pathologic capacity within pro-inflammatory ILC2s. In new preliminary studies, we uncovered a novel link between intracellular changes in the structural morphology of ILC2 mitochondria and the pro-inflammatory capacity within these cells that results in lung airway inflammation. We found that upon exposure to lung tissue inflammatory signals, ILC2s increased mitochondrial mass and remodeled their mitochondrial morphology network from a state of elongated `fusion' to fragmented `fission'. Furthermore, we found that inhibition of fission during a murine model of papain allergen exposure strongly curtailed ILC2 responses and altered their metabolic programming, thereby resulting in protection from severe lung inflammation. However, despite these advances, fundamental gaps in knowledge remain about 1) how remodeling of mitochondrial network morphology affects ILC2-intrinsic airway inflammation and 2) the identification of the metabolic mechanisms by which mitochondrial dynamics control ILC2 pro-inflammatory function. Here I propose two Aims consisting of cutting-edge techniques in cellular metabolism and immunobiology to dissect the role of mitochondrial morphology dynamics in controlling ILC2 metabolic programming and pathological function during murine and human allergic airway inflammation.

项目摘要 仅在美国，哮喘就会影响约2400万人，其中600万是儿童 18岁，每年造成3,000多人死亡1,2。一个免疫细胞种群，称为第2组 先天淋巴样细胞（ILC2）是驱动肺部炎性疾病不可或缺的，包括哮喘 响应组织“警报”细胞因子信号的2型细胞因子的产生。尽管在ILC2上取得了这些进步 功能，我们对控制这种病理的细胞内途径的知识有一个根本的差距 促炎性ILC2的容量。在新的初步研究中，我们发现了 ILC2线粒体的结构形态和促炎能力的细胞内变化 在这些细胞中导致肺气道炎症。我们发现暴露于肺组织时 炎症信号，ILC2增加了线粒体质量并重塑了线粒体形态 从细长的“融合”状态到碎片的“裂变”的网络。此外，我们发现抑制 帕帕因过敏原暴露鼠模型期间的裂变强烈限制了ILC2的反应并改变了其 代谢编程，从而防止严重的肺部炎症。但是，尽管如此 进步，知识的基本差距仍然大约是1）线粒体网络的重塑方式 形态会影响ILC2内膜气道炎症，2）通过 线粒体动力学控制ILC2促炎功能。在这里，我提出了两个目标，包括 细胞代谢和免疫生物学中的尖端技术剖析线粒体的作用 控制ILC2代谢编程和病理功能的形态动力学和 人过敏性气道炎症。