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

项目总结/摘要 严重哮喘难以控制，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，女性的严重哮喘发生率高于男性。 严重的，未控制的哮喘患者可能有2型嗜酸性粒细胞免疫介导的气道炎症， 响应或可能具有增加的由IL-17 A和/或IFN-γ驱动的嗜酸性粒细胞驱动的气道炎症。 通过雄激素受体（AR）发出信号的替吉奥可降低小鼠的气道炎症。 雾化吸入脱氢表雄酮-3-硫酸酯（DHEA-S），一种雄激素，可改善中度至重度哮喘患者的哮喘控制。 严重哮喘患者的II期随机临床试验。然而，AR的机制 信号转导降低哮喘中Th 2和Th 17驱动的气道炎症仍不清楚。我的化验结果显示 AR信号减少Th 2和Th 17驱动的炎症，增加小鼠Treg稳定性， 与严重哮喘的女性相比，严重哮喘的女性循环Th 17细胞显著减少 哮喘，CD 4 + T辅助细胞有不同的代谢模式，Th 17和Th 2依赖于 氨解和糖酵解代谢以及依赖氧化磷酸化的TdR。此外，我的实验室 先前的研究表明，在患有支气管肺泡灌洗液中， 哮喘和严重哮喘患者的循环T细胞的标记物表达增加， 氨解和糖酵解。我的初步数据显示AR信号降低了代谢功能 通过减少小鼠Th 2和Th 17细胞中的β-氨基解和糖酵解。此外，雄性小鼠 屋尘螨（HDM）诱导气道炎症降低了与 与雌性小鼠相比，氯胺酮溶解。最近的研究表明，let 7 microRNA家族减少了 在B细胞和CD 8 T细胞中的糖酵解和精氨酸分解过程。Let 7 f是let 7 f miRNA家族的一员， Th 17中IL-17 A和IL-23 R表达下调，我们的实验室显示卵巢激素减少 雄激素5α-DHT可增加Th 17细胞let 7 f的表达。因此，T细胞的代谢变化 可以解释在严重的，不受控制的哮喘中看到的炎症环境的变化。基于这些 研究结果，我假设AR信号减少了T辅助细胞中的β-氨基分解和糖酵解，导致 降低Th 2和Th 17介导的气道炎症。在这个建议中，我将：（1）确定AR信令如何 降低T辅助细胞的代谢以限制气道炎症，以及（2）阐明AR信号传导如何 促进let 7 f对T辅助细胞代谢和分化的负调节。这些研究将 证明了性激素调节CD 4 + T细胞生物学的基本机制， 发现并提供新的潜在疗法的证据，包括DHEA-S或代谢抑制剂， CB 839，使用免疫代谢创新技术治疗不受控制的重度哮喘患者。

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.