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 2

AR signaling increases the suppressive function of Tregs during ongoing allergic airway inflammation.

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AR signaling increases the suppressive function of Tregs during ongoing ...
(A) Experimental model for OVA-induced allergic airway inflammation with adoptive transfer of OVA-specific iTregs from DO11.10 Foxp3EGFP male or female mice and T effectors from DO11.10 female mice. (B) Representative dot plots showing OVA-specific iTregs and IL-13 production in lungs of recipient mice. Cells were pre-gated on viable, CD3+CD4+ cells. (C and D) Quantification of OVA-specific iTregs and IL-13+CD4+ T cells in lungs of recipient mice. (E) Percentage of eosinophils in BAL fluid from recipient mice. (B–E) Data are expressed as mean ± SEM; n = 9–11 from 2 separate experiments. *P < 0.05, ANOVA with Tukey’s post hoc analysis. (F–I) Arfl/0 and Arfl/0 Foxp3Cre+ male mice were intranasally challenged with Alt Ext, and BAL and lungs were harvested 1 day after the last challenge. (F and G) Whole-lung IL-13 and IL-5 levels. (H and I) BAL eosinophil and neutrophil cell counts. Data are expressed as mean ± SEM; n = 4–6. *P < 0.05, Student’s t test. (J–L) Arfl/0 and Arfl/0 Foxp3Cre+ male mice were intranasally challenged with Alt Ext or PBS, and lungs were harvested 2 days after the last Alt Ext or PBS challenge for airway physiology or histology. (J) Airway resistance to increasing concentrations of nebulized methacholine (Mch) was determined. (K and L) Airway inflammation. Whole lungs were stained with H&E, and airway inflammation was scored. Original magnification of images, ×10. (J–L) Data are expressed as mean ± SEM; n = 3–4. *P < 0.05, ANOVA with repeated analysis and Tukey’s post hoc test for J and ANOVA with Tukey’s post hoc analysis for L.