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.
Highlights
While androgen receptor (AR) signaling directly suppressed ILC2 proliferation and cytokine expression [41, 42, 44, 45], AR signaling did not directly decrease CD4+ Th2 cell cytokine production [40]. These results suggest that AR signaling attenuates type 2 inflammation through additional, undescribed pathways
We focused on a new pathway of suppression in allergic airway inflammation and determined whether AR signaling increased Treg suppressive function to downregulate Alternaria extract (Alt Ext)–induced allergic airway inflammation
We examined the percentage of Bcl6+ Tregs after recombinant mouse IL-33 (rmIL-33) administration and determined that Tregs from B6 Foxp3EGFP male mice had increased Bcl6 expression compared with female B6 Foxp3EGFP female and ArTfm Foxp3EGFP male mice (Supplemental Figure 8)
Summary
A sex bias exists in many autoimmune diseases and chronic inflammatory disorders, including asthma. Females have increased asthma prevalence compared with males. Increased production of dehydroepiandrosterone (DHEA), an androgen, occurs during puberty in males more than females, and higher sulfonated DHEA (DHEA-S) levels positively correlated with increases in lung function in the Severe Asthma Research Program I, II, and III cohorts [4, 5]. Phase II clinical trials showed that nebulized or slow-release oral administration of DHEA to males and females with severe asthma decreased asthma symptoms and increased lung function [4, 6]. These clinical data suggest that AR signaling attenuates allergic airway inflammation
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