Clec5a regulation of Macrophage function in COPD

描述(由申请人提供)：暴露于香烟烟雾(CS)对健康的影响和经济负担是压倒性的。对健康的主要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，还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，研究主要集中在氧化应激和与巨噬细胞和中性粒细胞功能相关的蛋白降解失衡的病理上。虽然这些白细胞的重要性和它们的效应器功能已经被很好地记录下来，但导致它们被CS异常激活的机制却鲜为人知。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，证明CLEC5A激活受体在COPD的巨噬细胞激活中起作用。我们的初步研究表明，表达在肺泡巨噬细胞上的CLEC5A在CS暴露后巨噬细胞的激活中起着不可或缺的作用。我们产生了一种Clec5a缺陷的小鼠品系，揭示了CLEC5A在CS暴露后巨噬细胞激活和肺损伤中的重要作用。缺乏clec5a基因的小鼠未能出现COPD的显著特征，包括肺部炎症、巨噬细胞聚集和肺泡扩大。此外，利用一种新的CLEC5A受体融合蛋白和表达CLEC5A的报告细胞系，我们提供了证据表明，在CS暴露的肺上皮细胞上表达了一个以前未发现的独特的CLEC5A配体。这些发现提示了一种新的机制，促进了对CS暴露的呼吸道炎症和病理反应。

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.