Estrogen receptor-α signaling increases allergen-induced IL-33 release and airway inflammation

Background 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-alpha (ER-alpha,Esr1) or ER-beta (Esr2) increased ILC2-mediated airway inflammation. We hypothesize that estrogen signaling increases allergen-induced IL-33 release, ILC2 cytokine production, and airway inflammation. Methods FemaleEsr1(-/-), Esr2(-/-), wild-type (WT), and IL33(fl/fl)eGFP mice were challenged withAlternariaextract (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 andEsr1(-/-)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 17 beta-estradiol (E2), propyl-pyrazole-triol (PPT, ER-alpha agonist), or diarylpropionitrile (DPN, ER-beta agonist) before allergen challenge to determine IL-33 gene expression and release, extracellular ATP release, DUOX-1 production, and necrosis. Results Alt Ext challengedEsr1(-/-), but notEsr2(-/-),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 challengedEsr1(-/-)mice compared to WT mice. 17 beta-E2 or PPT, but not DPN, increased IL-33 gene expression, release, and DUOX-1 production in hBE33 or NHBE cells. Conclusion Estrogen receptor -alpha signaling increased IL-33 release and ILC2-mediated airway inflammation.