Origin and Function of Intra-epithelial Mast Cells in Asthma

哮喘上皮内肥大细胞的起源和功能

• 批准号: 10376361
• 负责人: TEAL S HALLSTRAND
• 金额: $ 74.14万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10376361
• 关键词: 3-Dimensional; Address; Air; Allergens; Allergic; Asthma; Cell physiology; Cells; Cellular biology; Child; Chymase; Coculture Techniques; Cross-Sectional Studies; Development; Disease; Disease Progression; Effector Cell; Epithelial; Epithelial Cells; Exercise; Gene Expression; Genomic approach; Goals; House Dust Mite Allergens; Immune response; Individual; Infiltration; Inflammation; Lead; Link; Location; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Target; Patients; Phenotype; Population; Pyroglyphidae; Research; Sampling; Severities; Source; Submucosa; Three-Dimensional Imaging; airway epithelium; airway hyperresponsiveness; asthma model; asthmatic airway; cytokine; design; immunopathology; in vivo; in vivo Model; intraepithelial; lipid mediator; mast cell; mouse model; novel; peripheral blood; prevent; progenitor; quantitative imaging; receptor; recruit; response; stem cells

Project Summary Airway hyperresponsiveness (AHR) is a fundamental feature of asthma and is the hallmark of the disease in the majority of patients with asthma. Our lab has been working to understand the underlying immunopathogenesis of AHR and recently discovered using three-dimensional quantitative imaging of the airway wall that in asthma there is a shift in mast cells (MC)s from the submucosa to the airway epithelium that is closely related to the severity of AHR as well as features of type-2 (T2) inflammation. This shift is critical as we identified a IL-33 dependent feed-forward loop in which MCs regulate the expression of epithelial IL-33 (IL33), indicating that MCs serve not only as effector cells but also regulate T2 inflammation through IL-33. This feed-forward loop is accentuated in airway epithelial cells (AEC)s from individuals with asthma indicating that the unique microenvironment that is established by the epithelium in asthma is critical for the propagation of AHR and T2 inflammation through this feed-forward interaction between MCs and the airway epithelium. The major goals of this research are to identify the underlying basis for MC infiltration of the airway epithelium, the molecular details of this interaction between MCs and primary AECs from individuals with asthma and the in vivo relevance of the IL-33-MC-axis using selected murine models of asthma. Given that mature MCs arise from circulating progenitors, we hypothesize that the number of MC progenitors (MCP)s in the airways is increased in asthma, and these cells function in concert with the susceptible airway epithelium to orchestrate T2 inflammation. We will directly address our hypothesis by using airway samples and primary AECs from individuals with and without asthma and/or allergic sensitization, combined with AEC- MC coculture models, and murine models of asthma in which we examine the function of the IL-33-MC-axis. In specific aim 1, we investigate the differences in the number and proliferation potential of MCPs in the airways and peripheral blood of subjects with asthma and AHR, relative to non-asthmatic control subjects with and without allergic sensitization. We further examine the expansion of MCPs in the airways following allergen challenge in individuals with asthma. In specific aim 2, we determine how the asthmatic airway epithelium interacts with MCs to regulate T2 inflammation, using an ex vivo model of primary AECs from subjects with and without asthma to examine this feed-forward mechanism. In specific aim 3, we use selective IL-33 receptor deletion in MCs in an in vivo model to understand how IL-33 acts through MCs to regulate the development of T2 inflammation and AHR. The completion of these studies using airway samples, phenotyped AECs, and sophisticated murine models will move the field forward through a better understanding of the interplay between AECs and intraepithelial MCs that serve to regulate AHR and the T2 immune response.

项目摘要 气道高反应性（AHR）是哮喘的基本特征，是该病的标志 大多数哮喘患者。我们的实验室一直在努力了解基础 AHR的免疫发病发生，最近使用三维定量成像发现 气道壁在哮喘中有肥大细胞（MC）从粘膜胶体转移到气道上皮的变化 与AHR的严重程度以及2型（T2）炎症的特征密切相关。这种转变至关重要 我们确定了IL-33依赖性馈电环，其中MCS调节上皮IL-33的表达 （IL33），表明MC不仅用作效应细胞，而且还通过IL-33调节T2炎症。 此馈送环在气道上皮细胞（AEC）中突出了哮喘的个体，表明 上皮在哮喘中建立的独特微环境对于传播至关重要 通过MC和气道上皮之间的这种馈送相互作用，AHR和T2炎症的炎症。 这项研究的主要目标是确定MC渗透气道的基本基础 上皮，MCS与个体初级AEC之间这种相互作用的分子细节 使用选定的哮喘鼠模型IL-33-MC轴哮喘和体内相关性。 鉴于成熟的MC是由循环祖细胞引起的，我们假设MC祖细胞数量 （MCP）在哮喘中增加了气道中的S，并且这些细胞与易感气道协同起作用 上皮来编排T2炎症。我们将通过使用气道样本直接解决我们的假设 以及来自和/或没有哮喘和/或过敏反应的人的主要AEC，与AEC相结合 MC结合模型和哮喘的鼠模型，其中我们检查了IL-33-MC轴的功能。在 具体目标1，我们研究了MCP在气道中的数量和增殖潜力的差异 与哮喘和AHR受试者的外周血相对于非心律对照受试者的血液和 没有过敏反应。我们进一步研究过敏原后气道中MCP的扩展 哮喘患者的挑战。在特定目标2中，我们确定哮喘气道上皮 与MCS相互作用以调节T2炎症，使用来自和和 没有哮喘来检查这种前进机制。在特定的目标3中，我们使用选择性IL-33受体 在体内模型中删除MC中的MC，以了解IL-33如何通过MC进行调节 T2发炎和AHR。使用气道样本，表型AEC和 精致的鼠模型将通过更好地理解相互作用的方式向前推动该领域 在调节AHR和T2免疫反应的AEC和​​上皮内MC之间。