Immune Mediators of IL-22 Signaling Alter Allergic Airway Disease

项目概要 过敏性哮喘影响全球约 3 亿人。随着哮喘发病率持续上升 上升，将免疫和病理生理机制与哮喘内型联系起来的研究非常重要 建立更有针对性、更有效的治疗方法。严重的类固醇不敏感（非嗜酸性粒细胞）哮喘 占当前疾病负担的一半以上，但很少有研究关注这一点的建模 疾病子集。在严重难治性疾病中，过敏原特异性、类固醇不敏感 T 辅助细胞 (Th)17 和/或 Th2 人们认为细胞对哮喘发病机制至关重要，导致肺部炎症、粘液 分泌过多和气道高反应性。 Th17 免疫细胞因子白细胞介素 (IL)-22 在 维持上皮完整性和促进修复的作用。 IL-22 受体 α-2 (IL-22Ra2)，一种可溶性 IL-22 受体，抑制其活性。 IL-22和内源性IL-22Ra2的意义以及 在严重哮喘中调节它们的途径尚不清楚。除了 IL-22Ra2、I 型干扰素 (IFN)、 由 IFNα 亚型和 IFNβ 组成，是在某些情况下改变 IL-10 和 IL-22 信号传导的免疫调节剂 炎症性疾病背景。根据我们的初步和已发表的研究结果，我们假设 IL- 22Ra2 和 I 型干扰素通过阻断 IL-22 信号传导使严重过敏性气道疾病 (AAD) 长期存在， 这是缓解 AAD 和维持肺上皮完整性所必需的。将实现以下目标 研究这一假设：1) 研究 IL-22Ra2 是否通过改变 IL-22 来调节严重的 AAD 肺中的生物利用度，2) 确定 I 型 IFN 是否通过诱导 IL-22Ra2 和限制来促进严重的 AAD 肺部的 IL-22 活性，以及 3) 检查肺部上皮细胞中的 IL-22 信号传导是否可以缓解严重的 AAD 并维持肺上皮的完整性。本申请中拟议的工作将开拓调查 深入研究 IL-22Ra2 和 I 型干扰素作为过敏性疾病调节剂的作用，并将揭示其潜力 IL-22 轴在 AAD 期间保护肺上皮的分子机制。这部小说作品在 临床前动物模型和人体样本将发现治疗重症的新治疗靶点 对标准疗法反应不佳的哮喘。

PROJECT SUMMARY Allergic asthma affects approximately 300 million people worldwide. As the incidence of asthma continues to rise, studies linking immune and pathophysiologic mechanisms to asthma endotypes are of great importance to establish more targeted and effective therapies. Severe, steroid-insensitive (non-eosinophilic) asthma accounts for greater than half the current disease burden, but few studies have focused on modeling this disease subset. In severe refractory disease, allergen-specific, steroid-insensitive T helper (Th) 17 and/or Th2 cells are thought to critically orchestrate asthma pathogenesis, resulting in pulmonary inflammation, mucus hypersecretion, and airway hyperresponsiveness. The Th17 immune cytokine interleukin (IL)-22 plays a vital role in maintaining epithelial integrity and promoting repair. IL-22 receptor alpha-2 (IL-22Ra2), a soluble receptor for IL-22, inhibits its activity. The significance of IL-22 and endogenous IL-22Ra2, as well as the pathways that regulate them in severe asthma, are unknown. Aside from IL-22Ra2, type I interferons (IFN), consisting of IFNα subtypes and IFNβ, are immunomodulators that alter IL-10 and IL-22 signaling in certain inflammatory disease contexts. Based on our preliminary and published findings, we hypothesize that IL- 22Ra2 and type I IFNs perpetuate severe allergic airway disease (AAD) by blocking IL-22 signaling, which is necessary to alleviate AAD and maintain epithelial integrity in the lung. The following aims will investigate this hypothesis: 1) Investigate whether IL-22Ra2 modulates severe AAD by altering IL-22 bioavailability in the lung, 2) Determine if type I IFNs promote severe AAD by inducing IL-22Ra2 and limiting IL-22 activity in the lung, and 3) Examine if IL-22 signaling in the epithelium of the lung alleviates severe AAD and maintains epithelial integrity in the lung. The proposed work in this application will pioneer investigations into the role of IL-22Ra2 and type I interferons as regulators of allergic disease and will uncover the potential molecular mechanisms by which the IL-22 axis protects the lung epithelium during AAD. This novel work in a preclinical animal model and human samples will uncover new therapeutic targets for the treatment of severe asthma that is poorly responsive to standard therapies.