Clec5a regulation of Macrophage function in COPD

Clec5a 对 COPD 巨噬细胞功能的调节

• 批准号: 8696486
• 负责人: Michael Borchers
• 金额: $ 39.63万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696486
• 关键词: Address; Adoptive Transfer; Alveolar Macrophages; Antibodies; Binding; C Type Lectin Receptors; CCR; Cell Line; Chimeric Proteins; Chronic Bronchitis; Chronic Obstructive Airway Disease; Coculture Techniques; Data; Development; Disease; Disease Progression; Economic Burden; Epithelial Cells; Exhibits; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Health; Immunoprecipitation; Inflammation; Injury; Investigation; Laboratories; Lead; Leukocytes; Ligands; Lung; Macrophage Activation; Mass Spectrum Analysis; Mediating; Modeling; Molecular; Morbidity - disease rate; Mouse Strains; Mus; NK Cell Activation; Oxidative Stress; Pathology; Pathway interactions; Patients; Phenotype; Play; Pneumonia; Production; Public Health; Pulmonary Emphysema; Quality of life; Receptor Signaling; Regulation; Reporter; Research; Respiratory physiology; Role; Signal Pathway; Signal Transduction; Smoker; Stress; Surface; Symptoms; System; Testing; Therapeutic Intervention; Tissues; Up-Regulation; Work; airway inflammation; base; chemokine receptor; cigarette smoke-induced; cigarette smoking; cytokine; effective therapy; macrophage; migration; monocyte; mortality; neutrophil; novel; novel therapeutics; public health relevance; receptor; response

DESCRIPTION (provided by applicant): The health effects and economic burden associated with cigarette smoke (CS) exposure are overwhelming. The primary health effects are associated with symptoms of Chronic Obstructive Pulmonary Disease (COPD) including chronic bronchitis and emphysema. Currently, there are no effective therapies to deter disease progression in COPD patients. Over the last several decades, research has primarily focused on pathologies attributed to oxidative stress and the proteolytic imbalance associated with macrophage and neutrophil functions. Although the significance of these leukocytes and their effector functions are well documented, the mechanisms that lead to their aberrant activation by CS are poorly understood. The goal of our laboratory is to investigate the pathways whereby CS exposure activates pulmonary leukocytes. In this project, we present compelling evidence for a role of the CLEC5A activating receptor in macrophage activation in COPD. Our preliminary studies reveal that CLEC5A, expressed on alveolar macrophage, plays an integral role in macrophage activation following CS exposure. We generated a Clec5a-deficient mouse strain that reveals an essential role for CLEC5A in macrophage activation and pulmonary injury following CS exposure. The Clec5a-deficient mice fail to develop the hallmark features of COPD including pulmonary inflammation, macrophage accumulation and airspace enlargement. Furthermore, using a novel CLEC5A receptor fusion protein and CLEC5A-expressing reporter cell line, we provide evidence that a unique, previously undiscovered ligand for CLEC5A is expressed on CS-exposed pulmonary epithelial cells. These findings suggest a novel mechanism that promotes airway inflammation and pathologies in response to CS exposure.

描述（由申请人提供）：与香烟烟雾（CS）暴露相关的健康影响和经济负担是压倒性的。主要的健康影响与慢性阻塞性肺疾病（COPD）的症状有关，包括慢性支气管炎和肺气肿。目前，没有有效的疗法来阻止COPD患者的疾病进展。在过去的几十年中，研究主要集中在归因于氧化应激以及与巨噬细胞和中性粒细胞功能相关的蛋白水解失衡的病理上。尽管这些白细胞及其效应子功能的意义有充分的文献记录，但导致CS异常激活的机制知之甚少。我们实验室的目的是研究CS暴露激活肺白细胞的途径。在这个项目中，我们提供了令人信服的证据，证明了CLEC5A激活受体在COPD中的巨噬细胞激活中的作用。我们的初步研究表明，在肺泡巨噬细胞上表达的Clec5a在CS暴露后在巨噬细胞激活中起着不可或缺的作用。我们产生了CLEC5A缺乏的小鼠菌株，该菌株揭示了CS暴露后CLEC5A在巨噬细胞激活和肺损伤中的重要作用。缺乏CLEC5A的小鼠无法发展COPD的标志性特征，包括肺部炎症，巨噬细胞积累和空域增大。此外，使用新型的CLEC5A受体融合蛋白和表达CLEC5A的记者细胞系，我们提供了证据表明，在CS暴露的肺上皮细胞上表达了独特的，以前未发现的CLEC5A的配体。这些发现提出了一种新的机制，可促进气道炎症和病理，以应对CS暴露。