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.

中文翻译：

---

雄激素受体信号传导促进过敏性气道炎症期间 Treg 抑制功能

与男性相比，女性哮喘患病率更高。在哮喘中，过敏性气道炎症是由 IL-33 信号传导通过 ST2 引发的，导致 IL-4、IL-5 和 IL-13 产生增加以及嗜酸性粒细胞浸润。Foxp3 ⁺ Tregs 抑制过敏性气道炎症，ST2 ⁺ Tregs 促进过敏性气道炎症。临床研究表明，雄激素脱氢表雄酮 (DHEA) 可减轻患者的哮喘症状，小鼠研究表明，雄激素受体 (AR) 信号可减少过敏性气道炎症。然而 AR 信号传导对肺部 Tregs 的影响仍不清楚。使用 AR 缺陷和 Foxp3 命运图谱小鼠，我们确定 AR 信号通过稳定 Foxp3 ^{+ Tregs 并限制 ST2 +} ex-Treg 和 IL-13 ⁺ Th2的数量，在链格孢提取物（Alt Ext；过敏原）攻击期间增加 Treg 抑制细胞和前调节性T细胞。AR 信号还通过限制 ST2 转录因子Gata2的表达以及减少 Alt Ext 诱导的小鼠气道上皮细胞产生 IL-33 来减少小鼠中 Alt Ext 诱导的 ST2 + ^{Tregs 。}我们在人类细胞中证实了我们的发现，其中 5α-二氢睾酮 (DHT)（一种雄激素）可降低肺 Tregs 中 IL-33 诱导的 ST2 表达，并降低人支气管上皮细胞中 Alt Ext 诱导的 IL-33 分泌。我们的研究结果表明，AR 信号稳定了 Treg 抑制功能，为哮喘的性别差异提供了机制。