Clec5a regulation of Macrophage function in COPD

Clec5a 对 COPD 巨噬细胞功能的调节

• 批准号: 9247243
• 负责人: Michael Borchers
• 金额: $ 39.5万
• 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 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247243
• 关键词: Address; Adoptive Transfer; Alveolar Macrophages; Antibodies; Binding; C Type Lectin Receptors; 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; Knockout Mice; 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; Production; Public Health; Pulmonary Emphysema; Pulmonary Inflammation; Pulmonary Pathology; Quality of life; Receptor Activation; Receptor Signaling; Regulation; Reporter; Research; Role; Signal Pathway; Signal Transduction; Smoker; Stress; Surface; System; Testing; Therapeutic Intervention; Tissues; Up-Regulation; airway inflammation; base; chemokine receptor; cigarette smoke-induced; cigarette smoking; cytokine; effective therapy; environmental tobacco smoke exposure; macrophage; migration; monocyte; mortality; neutrophil; novel; novel therapeutics; persistent symptom; public health relevance; receptor; response; targeted treatment

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。主要健康影响与慢性阻塞性肺病（COPD）的症状有关，包括慢性支气管炎和肺气肿。目前，没有有效的治疗方法来阻止COPD患者的疾病进展。在过去的几十年里，研究主要集中在归因于氧化应激和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学上。虽然这些白细胞的意义和它们的效应器功能是有据可查的，但导致它们被CS异常激活的机制却知之甚少。我们实验室的目标是研究CS暴露激活肺白细胞的途径。在这个项目中，我们提出了令人信服的证据CLEC5A活化受体在COPD巨噬细胞活化中的作用。我们的初步研究表明，CLEC5A，肺泡巨噬细胞上表达，在巨噬细胞活化CS暴露后起着不可或缺的作用。我们产生了Clec5a缺陷型小鼠品系，其揭示了CLEC5A在CS暴露后的巨噬细胞活化和肺损伤中的重要作用。Clec5a缺陷小鼠未能发展出COPD的标志性特征，包括肺部炎症、巨噬细胞积聚和空域扩大。此外，使用一种新的CLEC5A受体融合蛋白和CLEC5A表达报告细胞系，我们提供的证据表明，一个独特的，以前未发现的CLEC5A配体表达CS暴露的肺上皮细胞。这些发现表明一种新的机制，促进气道炎症和病理反应的CS曝光。