Androgen receptor signaling promotes Treg suppressive function during allergic airway inflammation
Vivek D. Gandhi, … , R. Stokes Peebles Jr., Dawn C. Newcomb
Vivek D. Gandhi, … , R. Stokes Peebles Jr., Dawn C. Newcomb
Published January 13, 2022
Citation Information: J Clin Invest. 2022;132(4):e153397. https://doi.org/10.1172/JCI153397.
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Research Article Inflammation Pulmonology

Androgen receptor signaling promotes Treg suppressive function during allergic airway inflammation

Abstract

Women have higher prevalence of asthma compared with men. In asthma, allergic airway inflammation is initiated by IL-33 signaling through ST2, leading to increased IL-4, IL-5, and IL-13 production and eosinophil infiltration. Foxp3+ Tregs suppress and ST2+ Tregs promote allergic airway inflammation. Clinical studies showed that the androgen dehydroepiandrosterone (DHEA) reduced asthma symptoms in patients, and mouse studies showed that androgen receptor (AR) signaling decreased allergic airway inflammation. Yet the impact of AR signaling on lung Tregs remains unclear. Using AR-deficient and Foxp3 fate-mapping mice, we determined that AR signaling increased Treg suppression during Alternaria extract (Alt Ext; allergen) challenge by stabilizing Foxp3+ Tregs and limiting the number of ST2+ ex-Tregs and IL-13+ Th2 cells and ex-Tregs. AR signaling also decreased Alt Ext–induced ST2+ Tregs in mice by limiting expression of Gata2, a transcription factor for ST2, and by decreasing Alt Ext–induced IL-33 production from murine airway epithelial cells. We confirmed our findings in human cells where 5α-dihydrotestosterone (DHT), an androgen, decreased IL-33–induced ST2 expression in lung Tregs and decreased Alt Ext–induced IL-33 secretion in human bronchial epithelial cells. Our findings showed that AR signaling stabilized Treg suppressive function, providing a mechanism for the sex difference in asthma.

Authors

Vivek D. Gandhi, Jacqueline-Yvonne Cephus, Allison E. Norlander, Nowrin U. Chowdhury, Jian Zhang, Zachary J. Ceneviva, Elie Tannous, Vasiliy V. Polosukhin, Nathan D. Putz, Nancy Wickersham, Amrit Singh, Lorraine B. Ware, Julie A. Bastarache, Ciara M. Shaver, Hong Wei Chu, R. Stokes Peebles Jr., Dawn C. Newcomb

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Figure 8

5α-DHT decreases IL-33 secretion on human airway epithelial cells and reduces ST2 expression on human lung Tregs.

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5α-DHT decreases IL-33 secretion on human airway epithelial cells and re...
(A) Ar expression in human bronchial epithelial cells (HBEs) from male and female subjects (control and asthma participants are combined) in the GEO GSE4302 study with statistical analysis by Student’s t test. (B and C) hBE33 cells or primary, differentiated HBEs were treated for 24 hours with vehicle (Veh) or 5α-DHT (0–1 nM) and stimulated with Alt Ext (30 μg/mL) for 1 hour. IL-33 was measured in supernatants by ELISA. hBE33 cells, n = 4 from 2 separate experiments; HBEs from male asthmatic individuals, n = 3 donors. Data are mean ± SEM. *P < 0.05, ANOVA with Tukey’s post hoc analysis. (D and E) CD45+ cells isolated from excised human lungs were stimulated with anti-CD3 and anti-CD28 in the presence of 5α-DHT (1 nM), IL-33 (40 ng/mL), and/or vehicle for 24 hours. Tregs (CD3+CD4+Foxp3+) and Th2 cells (CD3+CD4+Gata3+) were pre-gated, and ST2 MFI was determined for each group. Histogram of ST2 in Tregs or Th2 cells is shown. Data are mean ± SEM; n = 6 female and 5 male donors. *P < 0.05, ANOVA with Tukey’s post hoc analysis.