Keselman Aleksander, Fang Xi, White Preston B, Heller Nicola M
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205
J Immunol. 2017 Sep 1;199(5):1573-1583. doi: 10.4049/jimmunol.1601975. Epub 2017 Jul 31.
Allergic asthma is a chronic Th2 inflammation in the lungs that constricts the airways and presents as coughing and wheezing. Asthma mostly affects boys in childhood and women in adulthood, suggesting that shifts in sex hormones alter the course of the disease. Alveolar macrophages have emerged as major mediators of allergic lung inflammation in animal models as well as humans. Whether sex differences exist in macrophage polarization and the molecular mechanism(s) that drive differential responses are not well understood. We found that IL-4-stimulated bone marrow-derived and alveolar macrophages from female mice exhibited greater expression of M2 genes in vitro and after allergen challenge in vivo. Alveolar macrophages from female mice exhibited greater expression of the IL-4Rα and estrogen receptor (ER) α compared with macrophages from male mice following allergen challenge. An ERα-specific agonist enhanced IL-4-induced M2 gene expression in macrophages from both sexes, but more so in macrophages from female mice. Furthermore, IL-4-stimulated macrophages from female mice exhibited more transcriptionally active histone modifications at M2 gene promoters than did macrophages from male mice. We found that supplementation of estrogen into ovariectomized female mice enhanced M2 polarization in vivo upon challenge with allergen and that macrophage-specific deletion of ERα impaired this M2 polarization. The effects of estrogen are long-lasting; bone marrow-derived macrophages from ovariectomized mice implanted with estrogen exhibited enhanced IL-4-induced M2 gene expression compared with macrophages from placebo-implanted littermates. Taken together, our findings suggest that estrogen enhances IL-4-induced M2 gene expression and thereby contributes to sex differences observed in asthma.
过敏性哮喘是一种肺部的慢性Th2炎症，会使气道收缩，表现为咳嗽和喘息。哮喘在儿童期主要影响男孩，在成年期主要影响女性，这表明性激素的变化会改变疾病进程。在动物模型和人类中，肺泡巨噬细胞已成为过敏性肺部炎症的主要介质。巨噬细胞极化是否存在性别差异以及驱动不同反应的分子机制尚不清楚。我们发现，来自雌性小鼠的IL-4刺激的骨髓来源巨噬细胞和肺泡巨噬细胞在体外以及体内过敏原攻击后表现出更高的M2基因表达。与过敏原攻击后雄性小鼠的巨噬细胞相比，雌性小鼠的肺泡巨噬细胞表现出更高的IL-4Rα和雌激素受体（ER）α表达。一种ERα特异性激动剂增强了两性巨噬细胞中IL-4诱导的M2基因表达，但在雌性小鼠的巨噬细胞中增强得更多。此外，与雄性小鼠的巨噬细胞相比，来自雌性小鼠的IL-4刺激的巨噬细胞在M2基因启动子处表现出更多转录活性的组蛋白修饰。我们发现，向卵巢切除的雌性小鼠补充雌激素可在过敏原攻击后增强体内的M2极化，而巨噬细胞特异性缺失ERα会损害这种M2极化。雌激素的作用是持久的；与植入安慰剂的同窝小鼠的巨噬细胞相比，植入雌激素的卵巢切除小鼠的骨髓来源巨噬细胞表现出增强的IL-4诱导的M2基因表达。综上所述，我们的研究结果表明，雌激素增强IL-4诱导的M2基因表达，从而导致哮喘中观察到的性别差异。
