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 1

AR signaling decreases allergic airway inflammation and increases Treg suppressive function.

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AR signaling decreases allergic airway inflammation and increases Treg s...
(A) Experimental design of Alt Ext intranasal challenge model in B6-Foxp3EGFP female, B6-Foxp3EGFP male, and ArTfm Foxp3EGFP male mice. (B and C) Eosinophil and neutrophil counts in BAL fluid. (D) IL-13 protein expression in whole-lung homogenates. (E) Representative dot plots from Alt Ext–challenged mice displaying lung Tregs (Foxp3+CD4+ T cells) with quantitation to the right. (F) Representative dot plots from Alt Ext–challenged mice displaying lung Th2 cells (Gata3+CD4+ T cells) with quantitation to the right. In both E and F, cells were pre-gated on viable CD3+CD4+ T cells. FMO, fluorescence minus one. (G) Ratio of Tregs to Th2 cells in lungs of Alt Ext–challenged mice. (B–G) Data are expressed as mean ± SEM; n = 2–10 from 2 experiments. *P < 0.05, ANOVA with Tukey’s post hoc analysis. (H–J) Treg suppression assay using Tregs from B6-Foxp3EGFP female, B6-Foxp3EGFP male, or ArTfm Foxp3EGFP male mice and T effector cells from B6-Foxp3EGFP female mice. (H) Representative samples of T effector cell (Teff) proliferation at 1:2 Treg/T effector ratio. (I and J) Representative experiment and percentage suppression of Tregs at various ratios. (H–J) Data are expressed as mean ± SEM; n = 6–8 from 3 experiments. *P < 0.05, ANOVA with Tukey’s post hoc analysis.