Pulmonary, Critical Care and Sleep Medicine, The Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, Ohio, USA.
Department of Molecular Biology, University of Bergen, Bergen, Norway.
JCI Insight. 2019 Feb 21;4(4). doi: 10.1172/jci.insight.124710.
Allergic eosinophilic asthma is a chronic condition causing airway remodeling resulting in lung dysfunction. We observed that expression of sirtuin 2 (Sirt2), a histone deacetylase, regulates the recruitment of eosinophils after sensitization and challenge with a triple antigen: dust mite, ragweed, and Aspergillus fumigatus (DRA). Our data demonstrate that IL-4 regulates the expression of Sirt2 isoform 3/5. Pharmacological inhibition of Sirt2 by AGK2 resulted in diminished cellular recruitment, decreased CCL17/TARC, and reduced goblet cell hyperplasia. YM1 and Fizz1 expression was reduced in AGK2-treated, IL-4-stimulated lung macrophages in vitro as well as in lung macrophages from AGK2-DRA-challenged mice. Conversely, overexpression of Sirt2 resulted in increased cellular recruitment, CCL17 production, and goblet cell hyperplasia following DRA challenge. Sirt2 isoform 3/5 was upregulated in primary human alveolar macrophages following IL-4 and AGK2 treatment, which resulted in reduced CCL17 and markers of alternative activation. These gain-of-function and loss-of-function studies indicate that Sirt2 could be developed as a treatment for eosinophilic asthma.
变应性嗜酸性粒细胞性哮喘是一种慢性疾病，可导致气道重塑，从而导致肺功能障碍。我们观察到，组蛋白去乙酰化酶 Sirtuin 2（Sirt2）的表达调节了三重抗原（尘螨、豚草和烟曲霉）致敏和激发后嗜酸性粒细胞的募集。我们的数据表明，IL-4 调节 Sirt2 同种型 3/5 的表达。AGK2 对 Sirt2 的药理抑制导致细胞募集减少、CCL17/TARC 减少和杯状细胞增生减少。体外 IL-4 刺激的肺巨噬细胞和 AGK2-DRA 挑战的小鼠肺巨噬细胞中，YM1 和 Fizz1 的表达在 AGK2 处理后减少。相反，Sirt2 的过表达导致 DRA 挑战后细胞募集、CCL17 产生和杯状细胞增生增加。IL-4 和 AGK2 处理后，原代人肺泡巨噬细胞中 Sirt2 同种型 3/5 上调，导致 CCL17 和替代激活标志物减少。这些功能获得和功能丧失研究表明，Sirt2 可以开发为治疗嗜酸性粒细胞性哮喘的药物。
