Androgens inhibit IL-33 production and airway inflammation

重症哮喘患者发病率高，利用了50%与哮喘相关的医疗保健 每年。IL-33通过其受体ST2(IL1RL1)信号驱动过敏性呼吸道 炎症、气道高反应性和粘液产生通过增加IL-4、IL-5和 IL-13由Th2、组2固有淋巴样细胞(ILC2)和其他类型的细胞产生。而当 抗IL-33是一种很有前途的哮喘治疗药物，对其调节途径有进一步的了解 这一途径可能会在这一患者群体中带来新的治疗选择。在上一次 在资助期，我们确定了卵巢激素如何增加IL-17A和2型介导的 严重哮喘的呼吸道炎症，这在女性中最常见。在…的过程中 这些研究还发现，雄激素受体(AR)信号减弱了Th17细胞 分化、ILC2增殖和过敏性呼吸道炎症。去性腺雄性小鼠 (缺乏雄激素)与激素完整组相比，Alt Ext诱导的IL-33也增加 雄鼠。然而，AR信号减弱变应原诱导的呼吸道的机制 炎症情况尚不清楚。雄激素通过AR传递的信号与 女性和男性哮喘患者的肺功能和哮喘症状评分降低。新的 这一应用的初步数据表明，AR信号可减少过敏性呼吸道 通过减少活性IL-33的释放，维持T调节细胞(Tregs)的炎症 稳定和抑制功能，限制Th2和ILC2细胞ST2的表达 IL-33介导的过敏性呼吸道炎症。我们假设AR信号传递后- 转录修饰IL-33以限制释放，通过以下方式抑制下游IL-33信号 抑制ST2表达和信号转导，稳定Treg抑制功能。为了测试这一点 假设，我们将使用原代、分化的支气管上皮细胞和来自 切除哮喘患者和男性哮喘患者的肺和淋巴结以及小鼠模型 哮喘：目的1)确定AR信号限制IL-33释放的机制 人支气管上皮细胞，目标2)描绘AR信号如何增强Treg稳定性 和在过敏性呼吸道炎症过程中的抑制功能，以及目的3)确定AR 信号通过减少Th2细胞上ST2的表达和下游信号来减少过敏反应 呼吸道发炎。阐明AR信号如何在维持IL-33释放的同时减弱IL-33的释放 肺Treg功能将是重症患者个性化治疗的关键 哮喘和其他可能由IL-33介导的疾病。

Severe asthma patients have a high morbidity and utilize >50% of asthma-related health care each year. IL-33 signaling through its receptor, ST2 (IL1RL1), drives allergic airway inflammation, airway hyperresponsiveness, and mucus production by increasing IL-4, IL-5, and IL-13 production from Th2, group 2 innate lymphoid cells (ILC2), and other cells types. While anti-IL-33 is a promising asthma therapeutic, additional understanding of pathways the regulate this pathway could lead to novel therapeutic options in this patient population. In the previous funding period, we determined how ovarian hormones increased IL-17A and type 2-mediated airway inflammation in severe asthma, which is most common in women. Through the course of these studies we also found that that androgen receptor (AR) signaling attenuated Th17 cell differentiation, ILC2 proliferation, and allergic airway inflammation. Gonadectomized male mice (which lack androgens) also had increased Alt Ext-induced IL-33 compared to hormonally intact male mice. Yet, the mechanisms by which AR signaling attenuates allergen-induced airway inflammation were unclear. Androgens signaling through the AR are associated with increased lung function and decreased asthma symptom scores in women and men with asthma. New preliminary data for this application suggest that AR signaling decreases allergic airway inflammation by decreasing the release of active IL-33, sustaining T regulatory cells (Tregs) stability and suppressive function, and decreasing ST2 expression on Th2 and ILC2 cells to limit IL-33-mediated allergic airway inflammation. We hypothesize that AR signaling post- transcriptionally modifies IL-33 to limit release, restrains downstream IL-33 signaling by inhibiting ST2 expression and signaling, and stabilizes Treg suppressive function. To test this hypothesis, we will use primary, differentiated bronchial epithelial cell and immune cells from the excised lungs and lymph nodes of women and men with asthma as well as mouse models of asthma to: Aim 1) Determine the mechanisms by which AR signaling limits IL-33 release from human bronchial epithelial cells, Aim 2) Delineate how AR signaling potentiates Treg stability and suppressive function during allergic airway inflammation, and Aim 3) Determine if AR signaling decreases ST2 expression and downstream signaling on Th2 cells to reduce allergic airway inflammation. Delineating how AR signaling attenuates IL-33 release while maintaining lung Treg function will be critical for personalizing therapies for women and men with severe asthma and potentially other IL-33-mediated diseases.