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.

项目概要 仅在美国，哮喘就影响了大约 2400 万人，其中 600 万人是 20 岁以下的儿童 18 岁，每年造成 3,000 多人死亡1,2。一群免疫细胞，称为第 2 组 先天性淋巴细胞 (ILC2) 是通过 响应组织“警报”细胞因子信号产生 2 型细胞因子。尽管 ILC2 取得了这些进展 功能，我们对控制这种病理的细胞内途径的了解存在根本差距 促炎 ILC2 内的能力。在新的初步研究中，我们发现了两者之间的新联系 ILC2线粒体结构形态和促炎能力的细胞内变化 这些细胞内会导致肺部气道炎症。我们发现，当暴露于肺组织时 炎症信号，ILC2 增加线粒体质量并重塑线粒体形态 网络从拉长的“融合”状态转变为支离破碎的“裂变”状态。此外，我们发现抑制 在木瓜蛋白酶过敏原暴露的小鼠模型中，裂变强烈抑制了 ILC2 反应并改变了它们的反应 代谢编程，从而防止严重的肺部炎症。然而，尽管有这些 尽管取得了进展，但关于 1）如何重塑线粒体网络的知识仍然存在根本差距 形态学影响 ILC2 固有气道炎症，2) 代谢机制的鉴定 其中线粒体动力学控制 ILC2 促炎功能。在这里我提出两个目标，包括 细胞代谢和免疫生物学的尖端技术来剖析线粒体的作用 形态动力学在小鼠和小鼠期间控制 ILC2 代谢编程和病理功能 人类过敏性气道炎症。