Role of Eosinophils in Airway Inflammation and Remodeling

在理解嗜酸性粒细胞(EOS)如何参与炎症和 哮喘受试者的重塑。缺乏这一领域的知识，很难制定出适当的 更好地治疗哮喘等异质性疾病的药物。我们的长期目标是理解 EOS促进哮喘发展的机制，特别是更严重的 表型。本项目1的目标是确定激活的EOS如何产生促炎和 与过敏性哮喘相关的重塑因子。中心假说是IL-3激活EOS以 产生1)促炎症细胞因子IL-1B和2)促纤维化膜蛋白信号素7A (SEMA7A)。我们认为，IL-1B促进了高炎性细胞因子IL-17的增加。 淋巴细胞在过敏反应的背景下。SEMA7A诱导成纤维细胞向成纤维方向分化 MyoFb，放大呼吸道重塑。我们的初步数据将允许我们通过以下方式检验这一假设 目的：1)检测节段性变应原刺激后大鼠肺内IL-17的表达 哮喘患者。检测外周血和气道EOS中IL-1B的释放，并连接IL-1B的释放 体内有IL-17表达，体外有EOS能力使CD4+T淋巴细胞增加IL-17。2) 明确IL-3诱导IL-1B的作用机制。分析的机制包括mrna。 稳定性和IL-1B通过炎性小体成熟。3)分析基因的表达和调控 测定SEMA7A对人肺泡巨噬细胞的影响。这个 方法是创新的，解决了归因于EOS的新功能。EOS释放生物活性IL-1B， 以及SEMA7A在EOS上的表达，都是新颖的。EOS在IL-17生产中的意义 SEMA7A在人类FB上的作用尚不清楚。这些机制将是 在IL-3激活的EOS中进行分析，体外或在节段性变应原挑战的背景下进行体内分析。后者 体内方法，模拟自然过敏性哮喘，可以说使我们的小组在能力上脱颖而出 分析人体的呼吸道EOS。这项拟议的研究具有重要意义，因为它有望推动我们的 了解嗜酸性粒细胞在哮喘中的作用以及嗜酸性粒细胞在重症哮喘发生发展中的作用 哮喘。最终，这些研究获得的知识将有助于确定新的潜在目标 对目前的治疗方法难以奏效的患者的需求药物。 相关性(请参阅说明)： 我们认为IL-3通过以下途径参与哮喘的嗜酸性粒细胞功能：1)影响外周血中CD4+T细胞的产生 促炎症细胞因子IL-17；2)诱导肝纤维化分子信号素7A的表达。 对IL-3的关注是从目前以IL-5为靶向的治疗的范式转变。了解蜂窝和 IL-3激活嗜酸性粒细胞下游的生物分子机制将揭示新的途径 哮喘和其他嗜酸性粒细胞相关疾病的治疗意义。

There is a fundamental gap in understanding how eosinophils (EOS) participate in inflammation and remodeling in asthmatic subjects. The lack of knowledge in this field is problematic to develop appropriate drugs to better treat a heterogenic disease such as asthma. The long-term goal is to understand the mechanisms by which EOS contribute to the development of asthma, particularly the more severe phenotypes. The objective in this Project 1 is to identify how activated EOS produce pro-inflammatory and remodeling factors that are relevant in allergic asthma. The central hypothesis is that IL-3 activates EOS to produce 1) the pro-inflammatory cytokine IL-1B and 2) the pro-fibrotic membrane protein, semaphorin7A (SEMA7A). We propose that IL-1 B drives the increase of the highly inflammatory cytokine, IL-17 in lymphocytes in the context of an allergic response. SEMA7A induces fibroblasts (Fb) differentiation toward myoFb, amplifying airway remodeling. Our preliminary data will allow us to test this hypothesis by pursuing three specific aims: 1) Determine the expression of IL-17 in the ainways after segmental allergen challenge in patients with asthma. Measure IL-1B release from blood and ainway EOS, and connect the release of IL-1B with IL-17 expression in vivo and with EOS ability to increase IL-17 by CD4+ T lymphocytes in vitro. 2) Define the mechanisms responsible for IL-3-induced IL-1B. The mechanisms analyzed include mRNA stability and IL-1B maturation through the inflammasome. 3) Analyze the expression and regulation of SEMA7A on blood and ainway EOS and determine the effect of SEMA7A on human bronchial Fb. The approach is innovative addressing new functions attributed to EOS. The release of bioactive IL-1B by EOS, as well as the expression of SEMA7A on EOS, are both novel. The implication of EOS in IL-17 production has never been shown and the function of SEMA7A on human Fb is unknown. These mechanisms will be analyzed in IL-3-activated EOS in vitro or in vivo in the context of a segmental allergen challenge. This latter in vivo approach, which mimics natural allergic asthma, arguably sets our group apart in our abilities to analyze airway EOS in humans. The proposed research is significant because it is expected to advance our understanding ofthe role of EOS in asthma, and of EOS potential function in the development of severe asthma. Ultimately, the knowledge acquired by these studies, will help to define new potential targets for drugs in needs for patients refractory to current treatments. RELEVANCE (See instructions): We propose that IL-3 contributes to eosinophil function in asthma by 1) influencing CD4+ T cell production of the pro-inflammatory cytokine IL-17, and 2) inducing expression ofthe profibrotic molecule semaphorin 7 A. The focus on IL-3 is a paradigm shift from current IL-5-targeted therapies. Understanding the cellular and biomolecular mechanisms down-stream of eosinophil activation by IL-3 will reveal novel pathways with therapeutic implications in asthma and other eosinophils-related diseases.