Cephus Jacqueline-Yvonne, Gandhi Vivek D, Shah Ruchi, Brooke Davis Jordan, Fuseini Hubaida, Yung Jeffrey A, Zhang Jian, Kita Hirohito, Polosukhin Vasiliy V, Zhou Weisong, Newcomb Dawn C
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, USA.
Allergy. 2021 Jan;76(1):255-268. doi: 10.1111/all.14491. Epub 2020 Jul 26.
Group 2 innate lymphoid cells (ILC2) are stimulated by IL-33 to increase IL-5 and IL-13 production and airway inflammation. While sex hormones regulate airway inflammation, it remained unclear whether estrogen signaling through estrogen receptor-α (ER-α, Esr1) or ER-β (Esr2) increased ILC2-mediated airway inflammation. We hypothesize that estrogen signaling increases allergen-induced IL-33 release, ILC2 cytokine production, and airway inflammation.
Female Esr1 , Esr2 , wild-type (WT), and IL33 eGFP mice were challenged with Alternaria extract (Alt Ext) or vehicle for 4 days. In select experiments, mice were administered tamoxifen or vehicle pellets for 21 days prior to challenge. Lung ILC2, IL-5 and IL-13 production, and BAL inflammatory cells were measured on day 5 of Alt Ext challenge model. Bone marrow from WT and Esr1 female mice was transferred (1:1 ratio) into WT female recipients for 6 weeks followed by Alt Ext challenge. hBE33 cells and normal human bronchial epithelial cells (NHBE) were pretreated with 17β-estradiol (E2), propyl-pyrazole-triol (PPT, ER-α agonist), or diarylpropionitrile (DPN, ER-β agonist) before allergen challenge to determine IL-33 gene expression and release, extracellular ATP release, DUOX-1 production, and necrosis.
Alt Ext challenged Esr1 , but not Esr2 , mice had decreased IL-5 and IL-13 production, BAL eosinophils, and IL-33 release compared to WT mice. Tamoxifen decreased IL-5 and IL-13 production and BAL eosinophils. IL-33eGFP + epithelial cells were decreased in Alt Ext challenged Esr1 mice compared to WT mice. 17β-E2 or PPT, but not DPN, increased IL-33 gene expression, release, and DUOX-1 production in hBE33 or NHBE cells.
Estrogen receptor -α signaling increased IL-33 release and ILC2-mediated airway inflammation.
2型固有淋巴细胞（ILC2）受白细胞介素33（IL-33）刺激后会增加白细胞介素5（IL-5）和白细胞介素13（IL-13）的产生以及气道炎症。虽然性激素可调节气道炎症，但尚不清楚雌激素通过雌激素受体α（ER-α，Esr1）或雌激素受体β（ER-β，Esr2）发出的信号是否会增加ILC2介导的气道炎症。我们推测雌激素信号会增加变应原诱导的IL-33释放、ILC2细胞因子产生以及气道炎症。
用链格孢提取物（Alt Ext）或赋形剂对雌性Esr1、Esr2、野生型（WT）和IL33绿色荧光蛋白（eGFP）小鼠进行4天的激发。在特定实验中，小鼠在激发前21天给予他莫昔芬或赋形剂微丸。在Alt Ext激发模型的第5天，检测肺ILC2、IL-5和IL-13的产生以及支气管肺泡灌洗（BAL）炎性细胞。将WT和Esr1雌性小鼠的骨髓（1:1比例）移植到WT雌性受体中6周，随后进行Alt Ext激发。在变应原激发前，用17β-雌二醇（E2）、丙基吡唑三醇（PPT，ER-α激动剂）或二芳基丙腈（DPN, ER-β激动剂）预处理人支气管上皮细胞系hBE33细胞和正常人支气管上皮细胞（NHBE），以测定IL-33基因表达和释放、细胞外ATP释放、双氧化酶-1（DUOX-1）产生以及坏死情况。
与WT小鼠相比，经Alt Ext激发的Esr1小鼠（而非Esr2小鼠）IL-5和IL-13产生减少、BAL嗜酸性粒细胞减少以及IL-33释放减少。他莫昔芬可减少IL-5和IL-13产生以及BAL嗜酸性粒细胞。与WT小鼠相比，经Alt Ext激发的Esr1小鼠中IL-33eGFP+上皮细胞减少。17β-E2或PPT（而非DPN）可增加hBE33或NHBE细胞中IL-33基因表达、释放以及DUOX-1产生。
雌激素受体α信号增加IL-33释放以及ILC2介导 的气道炎症。
