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Estrogen receptor‐α signaling increases allergen‐induced IL‐33 release and airway inflammation
Author(s) -
Cephus JacquelineYvonne,
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.
Publication year - 2021
Publication title -
allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.363
H-Index - 173
eISSN - 1398-9995
pISSN - 0105-4538
DOI - 10.1111/all.14491
Subject(s) - estrogen receptor , endocrinology , medicine , estrogen receptor alpha , inflammation , estrogen , cytokine , immunology , cancer , breast cancer
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 IL33 fl/fl 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. 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.