Androgens inhibit IL-33 production and airway inflammation

重度哮喘患者的发病率高，且使用>50%的哮喘相关卫生保健 每年. IL-33通过其受体ST 2（IL 1 RL 1）的信号传导驱动过敏性气道 炎症、气道高反应性和粘液产生，通过增加IL-4、IL-5和 从Th 2、第2组先天淋巴样细胞（ILC 2）和其他细胞类型产生IL-13。而 抗IL-33是一种有前途的哮喘治疗药物， 该途径可能导致在该患者群体中的新的治疗选择。上一 在资助期间，我们确定了卵巢激素如何增加IL-17 A和2型介导的 严重哮喘中的气道炎症，这在女性中最常见。的战争 这些研究还发现，雄激素受体（AR）信号转导减弱了Th 17细胞， 分化、ILC 2增殖和过敏性气道炎症。性腺切除雄性小鼠 （缺乏雄激素）也增加了Alt Ext诱导的IL-33相比， 雄性老鼠然而，AR信号减弱过敏原诱导的气道炎症的机制， 炎症不清楚。通过AR的雄激素信号传导与增加 肺功能和哮喘症状评分降低的女性和男性哮喘患者。新 该应用的初步数据表明，AR信号传导降低了过敏性气道 通过减少活性IL-33的释放，维持调节性T细胞（T细胞） 稳定性和抑制功能，并降低Th 2和ILC 2细胞上的ST 2表达，以限制 IL-33介导的过敏性气道炎症。我们假设AR信号后- 转录修饰IL-33以限制释放，抑制下游IL-33信号传导， 抑制ST 2表达和信号传导，并稳定Treg抑制功能。为了验证这一 假设，我们将使用原代分化的支气管上皮细胞和免疫细胞， 切除患有哮喘的女性和男性的肺和淋巴结以及 目的：1）确定AR信号限制IL-33从哮喘中释放的机制。 人支气管上皮细胞，目的2）描述AR信号传导如何增强Treg稳定性 和抑制功能在过敏性气道炎症，目的3）确定是否AR 信号传导降低了ST 2表达和Th 2细胞上的下游信号传导，以减少过敏性 气道炎症描述AR信号传导如何减弱IL-33释放，同时维持 肺Treg功能对于患有严重肺结核的女性和男性的个性化治疗至关重要。 哮喘和潜在的其他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.