Androgen receptor signaling promotes Treg suppressive function during allergic airway inflammation

Abstract

Women have higher prevalence of asthma compared to 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 the androgen, dehydroepiandrosterone (DHEA), reduced asthma symptoms in patients, and mouse studies showed androgen receptor (AR) signaling decreased allergic airway inflammation. Yet, the role 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 and ex-Tregs. AR signaling also decreased Alt Ext-induced ST2+ Tregs in mice by limiting Gata2 expression, 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 5αdihydrotestosterone (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.

Sex differences in adult asthma and COPD therapy: a systematic review

“…AR signalling induced by androgens stabilizes CD4 + regulatory T cells (Tregs) suppressive function, providing a mechanism for higher prevalence of asthma in women compared with men [ 64 ]. This evidence is supported by the fact that the higher airway expression of AR and higher androgen levels in men are associated with better lung function, fewer symptoms, and a lower fraction exhaled nitric oxide (FeNO) in asthma [ 65 ].…”

Analysis of transcriptional changes in the immune system associated with pubertal development in a longitudinal cohort of children with asthma

“…However, a recent longitudinal study throughout adolescence found that asthma severity decreased equally in male and female subjects, probably due to increase in androgens in both sexes 47 . Androgen levels were found to be positively associated with increased pulmonary function 18,88 , as well as suppression of airway inflammation 89,90 . Due to the demographics of our cohort, we captured late pubertal stages in females, which are associated with increased incidence of asthma 14 , thus resulting in the sex-specific patterns of gene expression that we observed.…”

The use of androgen deprivation therapy for prostate cancer and its effect on the subsequent dry eye disease: a population-based cohort study

“…In previous study, the estrogen is associated with the elevation of interleukins and reactive oxygen species 30 . Besides, the relationship between androgen and the suppression of inflammatory reaction had been established 31 , 32 . However, there was no strong correlation between the androgen deficiency and the autoimmune disease, which indicated that the elevation of inflammatory process is not always cause inflammation-related disease.…”