Effects of androgen receptor (AR) signaling on CD4+ T cell metabolism during airway inflammation

项目摘要/摘要 严重哮喘很难控制，占哮喘相关医疗费用的大部分， 住院治疗。与哮喘的模式一致，女性的严重哮喘率高于男性。 严重的、失控的哮喘患者可能有由2型嗜酸细胞免疫介导的呼吸道炎症 由IL-17A和/或干扰素-驱动的中性粒细胞驱动的呼吸道炎症反应或可能增加。 通过雄激素受体(AR)传递信号的睾酮可以减少小鼠的呼吸道炎症。 雾化吸入脱氢表雄酮-3-硫酸酯(脱氢表雄酮-3-硫酸酯)，一种雄激素，在中到 II期随机临床试验中的重症哮喘患者。然而，AR的作用机制 信号转导减少Th2和Th17在哮喘中引起的呼吸道炎症仍不清楚。我的实验室显示 AR信号减少了Th2和Th17引发的炎症，并增加了小鼠Treg的稳定性 与患有严重哮喘的女性相比，严重哮喘患者的循环Th17细胞显著减少 哮喘，以及CD4+T辅助细胞有不同的代谢模式，Th17和Th2依赖于 谷氨酰胺分解和糖酵解代谢和Tregs依赖氧化磷酸化。此外，我的实验室 先前显示患者的支气管肺泡灌洗液中谷氨酰胺分解和糖酵解增加 哮喘患者及重症哮喘患者外周血中T细胞表面标志物的表达 谷氨酰胺分解和糖酵解。我的初步数据显示，AR信号会降低代谢功能 通过减少小鼠Th2和Th17细胞的谷氨酰胺分解和糖酵解。此外，雄性小鼠有 屋尘螨(HDM)诱导的呼吸道炎症降低了相关酶的表达 与雌性小鼠相比，谷氨酰胺分解作用更强。最近的研究表明，let7微RNA家族减少了 B细胞和CD8T细胞的糖酵解和谷氨酰胺分解过程。Let7f，let7f miRNA家族的成员， 下调Th17细胞IL-17A和IL-23R的表达，我们的实验室发现卵巢激素减少 雄激素5-α-dht可增加Th1 7细胞let7f的表达。因此，T细胞的代谢变化 可以解释严重的、无法控制的哮喘的炎症环境的变化。基于这些 发现，我假设AR信号减少T辅助细胞中的谷氨酰胺分解和糖酵解，导致 减少Th2和Th17介导的气道炎症。在本提案中，我将：(1)确定AR信令如何 降低T辅助细胞的新陈代谢以限制呼吸道炎症，以及(2)阐明AR信号如何 促进let7f对辅助性T细胞代谢和分化的负性调节。这些研究将 演示性激素调节CD4+T细胞生物学的基本机制以及 发现并为新的潜在疗法提供证据，包括脱氢表雄酮-S或代谢抑制剂，如 CB839，用于在免疫代谢方面使用创新技术的未受控制的严重哮喘患者。

PROJECT SUMMARY/ABSTRACT Severe asthma is difficult to control and accounts for the majority of asthma-related healthcare costs and hospitalizations. Consistent with patterns of asthma, severe asthma rates are higher in women than men. Severe, uncontrolled asthmatics may have airway inflammation mediated by a type 2, eosinophilic immune response or may have increased neutrophilic driven airway inflammation driving by IL-17A and/or IFN-. Testosterone, which signals through the androgen receptor (AR), decreases airway inflammation in mice. Nebulized dehydroepiandrosterone-3-sulfate (DHEA-S), an androgen, improved asthma control in moderate to severe asthma patients in a Phase II randomized clinical trial. However, the mechanisms by which AR signaling decreases Th2 and Th17 driven airway inflammation in asthma remains unclear. My labs showed that AR signaling decreased Th2 and Th17 driven inflammation and increased Treg stability in mice, that men with severe asthma have significantly decreased circulating Th17 cells compared to women with severe asthma, and that CD4+ T helper cells have distinct modes of metabolism, with Th17 and Th2 relying on glutaminolysis and glycolysis metabolism and Tregs relying on oxidative phosphorylation. Further, my labs previously showed increased glutaminolysis and glycolysis in bronchoalveolar lavage fluid from patients with asthma and circulating T cells from patients with severe asthma had increased expression of markers of glutaminolysis and glycolysis. My preliminary data shows that AR signaling decreases metabolic function through reductions in glutaminolysis and glycolysis in mouse Th2 and Th17 cells. Additionally, male mice with house dust mite (HDM) induced airway inflammation have decreased expression of enzymes related to glutaminolysis compared to female mice. Recent studies showed that the let7 microRNA family reduced glycolytic and glutaminolytic processes in B cells and CD8 T cells. Let7f, a member of the let7f miRNA family, downregulated IL-17A and IL-23R expression in Th17, and our lab showed that ovarian hormones decreased and 5α-DHT, an androgen, increased let7f expression in Th17 cells. Therefore, metabolic changes in T cells could explain the change in the inflammatory milieu seen in severe, uncontrolled asthma. Based on these findings, I hypothesize that AR signaling decreases glutaminolysis and glycolysis in T helper cells, resulting in decreased Th2 and Th17-mediated airway inflammation. In this proposal, I will: (1) determine how AR signaling decreases metabolism of T helper cells to limit airway inflammation, and (2) elucidate how AR signaling promotes the negative regulation of let7f on T helper cell metabolism and differentiation. These studies will demonstrate fundamental mechanisms by which sex hormones regulate CD4+ T cell biology as well as uncover and provide evidence for new potential therapeutics, including DHEA-S or metabolic inhibitors such as CB839, for patients with uncontrolled severe asthma using innovative techniques in immunometabolism.