Biology of IL-13 receptor Alpha-2 in Asthma

哮喘是一个主要的公共卫生问题，仅在美国就有1500万人受到影响。IL-13是一种 过敏性呼吸道疾病在人类和小鼠模型中的关键介体。它的多种功能有 由复杂的受体系统介导，包括IL-4R、IL-13R和IL-13R；2、IL-4R和IL-1。 13R&1形成高亲和力的信号异二聚体，与IL-13和信号特异性结合。相比之下，IL- 13R&2有一条短的细胞质尾巴，缺乏已知的信号基序，表明它没有直接的 信号能力。尽管亲和力很高，但IL-13R&2的表达不能赋予IL-13反应性 结合，以及大量的可溶性IL-13R&2的存在，甚至在幼小鼠中，表明IL-13R&2 13R&2是一种诱饵受体。事实上，IL-13R-2缺陷小鼠的特征已经揭示了IL-13R&2 可以通过隔离IL-13来下调IL-13的反应。尽管IL-13R&2显然在 下调IL-13的反应，有证据表明，IL-13R；2也可能导致过敏反应。 最近的研究表明，IL-13可以通过IL-13R；2发出信号，刺激转化生长因子介导的纤维化。 此外，我们自己的研究表明，IL-13R&2既可以促进也可以抑制糖尿病的发展。 呼吸道高反应性(AHR)和过敏性炎症。在小鼠体内，有明显的膜和 2.相反，我们实验室和其他实验室的最新数据支持人类缺乏的 可溶性IL-13R；2突出了膜IL-13R&2在人类中的潜在重要性。我们的数据 支持膜IL-13R；2可促进体内过敏性呼吸道高反应性。我们 假设膜和可溶性IL-13R；2在调节IL-13反应方面有不同的作用， 包括呼吸道高反应性和过敏性炎症的发展。为了解决这个问题 假设，我们已经建立了一个人源化的小鼠模型，在这个模型中，IL-13R&2只在小鼠中表达 肺，并且只以膜的形式存在。我们将使用这些小鼠，以及我们已经产生的小鼠 在他们的肺中独家表达可溶性IL-13R&2。我们还将利用原代和培养的人类细胞来 明确膜IL-13的作用2.IL-13途径是治疗干预的一个有吸引力的靶点 患有过敏性疾病。从鼠标系统中产生的数据得出的结论可能与 人类生物学，因为人类缺乏可察觉的可溶性血清IL-13R；2。 膜与可溶性IL-13R；2，使最有效的靶向治疗设计成为可能。

Asthma is a major public health problem affecting 15 million people in the United States alone. IL-13 is a critical mediator of allergic airway disease in humans and in mouse models. Its diverse functions are mediated by a complex receptor system that includes IL-4Rα, IL-13Rα1, and IL-13Rα2. IL-4Rα and IL- 13Rα1 form a high affinity signaling heterodimer that specifically binds IL-13 and signals. In contrast, IL- 13Rα2 has a short cytoplasmic tail that lacks known signaling motifs suggesting that it has no direct signaling ability. The inability of IL-13Rα2 expression to confer IL-13 responsiveness despite high affinity binding, and the presence of significant quantities of soluble IL-13Rα2, even in na¿ve mice, suggests that IL- 13Rα2 is a decoy receptor. Indeed, characterization of IL-13Rα2-deficient mice has revealed that IL-13Rα2 can downregulate IL-13 responses by sequestering IL-13. Although IL-13Rα2 clearly plays a role in downregulating IL-13 reponses, there is evidence that IL-13Rα2 may also contribute to allergic responses. Recent studies have shown that IL-13 can signal through IL-13Rα2 to stimulate TGFβ-mediated fibrosis. Furthermore, our own studies demonstrate that IL-13Rα2 can both promote and inhibit the development of airway hyperresponsiveness (AHR) and allergic inflammation. In mice, there are distinct membrane and soluble forms of IL-13Rα2. In contrast, recent data from our lab and others support that humans lack soluble IL-13Rα2 highlighting the potential importance of membrane IL-13Rα2 in humans. Our data support that membrane IL-13Rα2 can contribute to allergic airways hyperresponsiveness in vivo. We hypothesize that membrane and soluble IL-13Rα2 have distinct roles in regulating IL-13 responses, including the development of airway hyperresponsiveness and allergic inflammation. In order to address this hypothesis, we have generated a humanized mouse model in which IL-13Rα2 is expressed only in mouse lungs and only in the membrane form. We will use these mice, as well as mice that we have generated that exclusively express soluble IL-13Rα2 in their lungs. We will also utilize primary and cultured human cells to define the role of membrane IL-13Rα2. The IL-13 pathway is an attractive target for therapeutic intervention in allergic disorders. Conclusions derived from data generated in mouse systems are likely not relevant to human biology since humans lack appreciable soluble serum IL-13Rα2. It is critical to delineate the roles of membrane versus soluble IL-13Rα2 to enable the design of the most effective targeted therapies.