Wortham Brian W, Eppert Bryan L, Flury Jennifer L, Garcia Sara Morgado, Donica Walter R, Osterburg Andrew, Joyce-Shaikh Barbara, Cua Daniel J, Borchers Michael T
Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267; and.
Merck Research Laboratories, Palo Alto, CA 94304.
J Immunol. 2016 Apr 15;196(8):3227-31. doi: 10.4049/jimmunol.1500978. Epub 2016 Feb 29.
Chronic obstructive pulmonary disease (COPD) is a devastating disease with no effective therapies. We investigated the role of the C-type lectin receptor, CLEC5A, in macrophage activation and pulmonary pathogenesis in a mouse model of COPD. We demonstrate that CLEC5A is expressed on alveolar macrophages in mice exposed long-term to cigarette smoke (CS), as well as in human smokers. We also show that CLEC5A-mediated activation of macrophages enhanced cytokine elaboration alone, as well as in combination with LPS or GM-CSF in CS-exposed mice. Furthermore, usingClec5a-deficient mice, we demonstrate that CS-induced macrophage responsiveness is mediated by CLEC5A, and CLEC5A is required for the development of inflammation, proinflammatory cytokine expression, and airspace enlargement. These findings suggest a novel mechanism that promotes airway inflammation and pathologies in response to CS exposure and identifies CLEC5A as a novel target for the therapeutic control of COPD pathogenesis.
慢性阻塞性肺疾病（COPD）是一种尚无有效治疗方法的毁灭性疾病。我们在COPD小鼠模型中研究了C型凝集素受体CLEC5A在巨噬细胞活化和肺部发病机制中的作用。我们证明，长期暴露于香烟烟雾（CS）的小鼠以及人类吸烟者的肺泡巨噬细胞上均表达CLEC5A。我们还表明，CLEC5A介导的巨噬细胞活化不仅单独增强了细胞因子的分泌，而且在暴露于CS的小鼠中与LPS或GM-CSF联合使用时也增强了细胞因子的分泌。此外，使用Clec5a基因缺陷小鼠，我们证明CS诱导的巨噬细胞反应性是由CLEC5A介导的，并且CLEC5A是炎症发展、促炎细胞因子表达和肺泡腔扩大所必需的。这些发现提示了一种新机制，该机制可促进对CS暴露的气道炎症和病理反应，并将CLEC5A鉴定为COPD发病机制治疗控制的新靶点。
