Estrogen receptor-α signaling increases allergen-induced IL-33 release and airway inflammation
Jacqueline-Yvonne Cephus
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Search for more papers by this authorVivek D. Gandhi
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Search for more papers by this authorRuchi Shah
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Search for more papers by this authorJordan Brooke Davis
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Search for more papers by this authorHubaida Fuseini
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, USA
Search for more papers by this authorJeffrey A. Yung
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Search for more papers by this authorJian Zhang
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Search for more papers by this authorHirohito Kita
Allergic Diseases Research Laboratory, Mayo Clinic, Phoenix, Arizona, USA
Search for more papers by this authorVasiliy V. Polosukhin
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Search for more papers by this authorWeisong Zhou
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Search for more papers by this authorCorresponding Author
Dawn C. Newcomb
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
Correspondence
Dawn C. Newcomb, Vanderbilt University Medical Center, 1161 21st Avenue, T-1218 MCN, 1161 21st Avenue, T-1218 MCN, Nashville, TN 37232.
Email: [email protected]
Search for more papers by this authorJacqueline-Yvonne Cephus
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Search for more papers by this authorVivek D. Gandhi
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Search for more papers by this authorRuchi Shah
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Search for more papers by this authorJordan Brooke Davis
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Search for more papers by this authorHubaida Fuseini
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, USA
Search for more papers by this authorJeffrey A. Yung
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Search for more papers by this authorJian Zhang
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Search for more papers by this authorHirohito Kita
Allergic Diseases Research Laboratory, Mayo Clinic, Phoenix, Arizona, USA
Search for more papers by this authorVasiliy V. Polosukhin
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Search for more papers by this authorWeisong Zhou
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Search for more papers by this authorCorresponding Author
Dawn C. Newcomb
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
Correspondence
Dawn C. Newcomb, Vanderbilt University Medical Center, 1161 21st Avenue, T-1218 MCN, 1161 21st Avenue, T-1218 MCN, Nashville, TN 37232.
Email: [email protected]
Search for more papers by this authorAbstract
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-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.
Methods
Female Esr1-/-, Esr2-/-, wild-type (WT), and IL33fl/fleGFP 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.
Results
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.
Conclusion
Estrogen receptor -α signaling increased IL-33 release and ILC2-mediated airway inflammation.
Graphical Abstract
Allergen-induced airway inflammation is increased by estrogen signaling. Compared to WT mice, Alt Ext challenged Esr1 −/− mice have decreased IL-5 and IL-13 production, eosinophils number, and IL-33 release. Estrogen receptor-α signaling has no direct effect on ILC2 proliferation or cytokine expression. Abbreviations: Alt Ext, Alternaria extract; DPN, diarylpropionitrile; E2, 17β-estradiol; Eos, eosinophils; Esr1 −/−, estrogen receptor alpha deficient mice; ER-α, estrogen receptor α; ILC2, group 2 innate lymphoid cells; PPT, propyl-pyrazole-triol; WT, wild-type
CONFLICTS OF INTEREST
The authors have no conflict of interest in relation to this work.
Supporting Information
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| all14491-sup-0001-FigS1-S5.pdfPDF document, 986.9 KB | Figures S1-S5 |
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