雄激素受体信号在过敏性气道炎症中促进Treg抑制功能
2022/01/28
摘要
与男性相比，女性哮喘患病率较高。在哮喘中，过敏性气道炎症通过由ST2介导的IL-33信号传导引起的，导致IL-4、IL-5和IL-13产生增加和嗜酸性粒细胞浸润。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，而小鼠研究表明雄激素受体（AR）信号可减轻过敏性气道炎症。然而，AR信号在肺Tregs中的作用尚不清楚。通过AR缺陷和Foxp3命运图谱小鼠，我们发现，在链格孢菌提取物（Alt-Ext，过敏原）激发期间，AR信号通过稳定Foxp3+Tregs并限制ST2+ex-Tregs和IL-13+Th2及ex-Tregs的数量来增加Treg抑制。AR信号还通过限制ST2转录因子Gata2的表达，以及通过减少Alt-Ext诱导的小鼠气道上皮细胞产生IL-33，降低Alt-Ext诱导的小鼠ST2+Tregs。我们证实了我们在人类细胞中的发现，其中雄激素5α-二氢睾酮（DHT）降低了IL-33诱导的肺树突状细胞ST2表达，降低了Alt-Ext诱导的人支气管上皮细胞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。
Androgen receptor signaling promotes Treg suppressive function during allergic airway inflammation
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, Ray S Peebles Jr, Dawn C Newcomb
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 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.
与男性相比，女性哮喘患病率较高。在哮喘中，过敏性气道炎症通过由ST2介导的IL-33信号传导引起的，导致IL-4、IL-5和IL-13产生增加和嗜酸性粒细胞浸润。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，而小鼠研究表明雄激素受体（AR）信号可减轻过敏性气道炎症。然而，AR信号在肺Tregs中的作用尚不清楚。通过AR缺陷和Foxp3命运图谱小鼠，我们发现，在链格孢菌提取物（Alt-Ext，过敏原）激发期间，AR信号通过稳定Foxp3+Tregs并限制ST2+ex-Tregs和IL-13+Th2及ex-Tregs的数量来增加Treg抑制。AR信号还通过限制ST2转录因子Gata2的表达，以及通过减少Alt-Ext诱导的小鼠气道上皮细胞产生IL-33，降低Alt-Ext诱导的小鼠ST2+Tregs。我们证实了我们在人类细胞中的发现，其中雄激素5α-二氢睾酮（DHT）降低了IL-33诱导的肺树突状细胞ST2表达，降低了Alt-Ext诱导的人支气管上皮细胞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。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(J Clin Invest. 2022 Jan 13;e153397. doi: 10.1172/JCI153397.)
(J Clin Invest. 2022 Jan 13;e153397. doi: 10.1172/JCI153397.)
Androgen receptor signaling promotes Treg suppressive function during allergic airway inflammation
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, Ray S Peebles Jr, Dawn C Newcomb
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 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.
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赖氨酰氧化酶样2在哮喘中增加，并有助于哮喘气道重塑
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嗜酸性粒细胞在气道壁中的分布对于哮喘气道高反应性和T2炎症的特定特征至关重要
