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: 10599191
• 负责人: TEAL S HALLSTRAND
• 金额: $ 73.52万
• 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/10599191
• 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; Dryness; Effector Cell; Epithelial Cells; Epithelium; Exercise; Gene Expression; Genomic approach; Goals; House Dust Mite Allergens; Immune response; Individual; Infiltration; Inflammation; Lead; Link; Location; Mediating; Mediator; Modeling; Molecular; Molecular Target; Osmosis; Patients; Phenotype; Population; Predisposition; 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; proliferation potential; quantitative imaging; receptor; recruit; respiratory examination; respiratory imaging; 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，也是哮喘的标志。 大多数哮喘患者。我们的实验室一直致力于了解 AHR的免疫发病机制，最近发现使用三维定量成像的AHR， 在哮喘中，肥大细胞（MC）从粘膜下层转移到气道上皮， 与AHR的严重程度以及2型（T2）炎症的特征密切相关。这一转变至关重要， 我们确定了一个IL-33依赖性前馈回路，其中MC调节上皮IL-33的表达， （IL-33），表明MC不仅作为效应细胞，而且还通过IL-33调节T2炎症。 这种前馈回路在哮喘个体的气道上皮细胞（AEC）中被强化，表明 哮喘中上皮细胞建立的独特微环境对哮喘的传播至关重要， AHR和T2炎症通过MC和气道上皮之间的这种前馈相互作用。 本研究的主要目的是确定MC浸润气道的基础 上皮细胞，这种相互作用的分子细节MC和初级AEC从个人 使用选定的哮喘小鼠模型研究哮喘和IL-33-MC轴的体内相关性。 考虑到成熟的MC来自循环祖细胞，我们假设MC祖细胞的数量 哮喘患者气道中的单核细胞趋化蛋白（MCP）增加，这些细胞与易感气道协同作用 上皮细胞协调T2炎症。我们将通过使用气道样本直接解决我们的假设 以及来自患有和不患有哮喘和/或过敏性致敏的个体的原发性AEC，与AEC- MC共培养模型，和小鼠哮喘模型，其中我们检查IL-33-MC轴的功能。在 具体目标1，我们研究了气道中MCP的数量和增殖潜力的差异， 哮喘和AHR受试者的外周血，相对于非哮喘对照受试者， 无过敏性致敏。我们进一步研究了过敏原刺激后气道中MCP的扩增， 对哮喘患者的挑战。在具体目标2中，我们确定哮喘气道上皮细胞如何 与MC相互作用以调节T2炎症，使用来自患有和 来检验这种前馈机制。在具体目标3中，我们使用选择性IL-33受体， 在体内模型中的MC中的缺失，以了解IL-33如何通过MC作用来调节 T2炎症和AHR。使用气道样本、表型AEC和 通过更好地理解这种相互作用， AEC和上皮内MC之间的相互作用，其用于调节AHR和T2免疫应答。