ILC2 and epithelial cell heterogeneity and self-sustaining type 2 airway niches in asthma

项目摘要/摘要 这项资助旨在了解第二组先天淋巴样细胞(ILC2s)在维持上皮细胞改变中的作用 接口，这对于建立一个有助于持久化的异常重塑的利基环境至关重要 过敏性病理。这项提议得到了前一笔赠款支持的出版物的支持，展示了 (1)组织阐述的上皮细胞因子在组织2型免疫细胞激活中的关键作用，包括 ILC2；以及(2)在肠道中发现了驱动杯状细胞的前馈上皮-ILC2回路 增生和组织增生，为发现呼吸道中类似的回路提供了动力 系统。正如项目3中的同事所显示的那样，严重的、药物顽固性哮喘患者的比例不成比例 与持续粘液堵塞相关的相对固定的呼吸道异常的患者；显著的 个人也有复发性鼻息肉的比例。再加上我们在动物模型上的发现 系统，我们最重要的假设是，失调的上皮-ILC2在呼吸道循环， 包括鼻咽(NP)、气管和呼吸道，是过敏的持久性壁龛存在的基础 病理学是成立的。我们在老鼠身上使用了新的基因工具，允许对这种电路进行精细的解剖，我们 提出与PPG的总体目标一致的3个具体目标。首先，我们将定义ILC2环境 在小鼠的皮肤、NP、气管和肺中，我们在这些地方发现了意想不到的多样性 由PPG中的其他人扩展到人体研究。其次，我们将定义NP中的簇状细胞场景和 气管，因为这种神秘的上皮细胞的关键作用在我们的肠道研究中被发现。我们有 在人类变态反应性息肉中显示出绒毛细胞增生。第三，我们将使用小鼠皮肤模型 炎症后肺变应原激发以分析上皮-ILC2回路的发展 皮肤到NP再到肺，以及这些细胞各自的作用。这些发现将应用于人体组织。 在此PPG的核心B中收集并在此PPG的核心C中进行分析，以在重症患者中生成发现 哮喘。总而言之，这种PPG将揭示功能失调的细胞网络和持续过敏的利基 肺部的免疫病理学。

Project Summary / Abstract This grant seeks to understand the role of Group 2 innate lymphoid cells (ILC2s) in sustaining an altered epithelial interface that is crucial to the establishment of an aberrant remodeled niche that contributes to the persistence of allergic pathology. The proposal is underpinned by publications supported in the prior grant, demonstrating (1) a key role for tissue-elaborated epithelial cytokines in the activation of tissue type 2 immune cells, including ILC2s; and (2) discovery of a feed-forward epithelial-ILC2 circuit in the intestines that drives goblet cell hyperplasia and tissue hyperplasia, providing the impetus for uncovering similar circuitry in the respiratory system. As shown by colleagues in Project 3, severe, drug-recalcitrant, asthma is populated disproportionately with patients with relatively ‘fixed’ airway abnormalities associated with persistent mucus plugs; a significant proportion of individuals also have recurrent nasal polyposis. Together with our discoveries in model animal systems, our over-arching hypothesis is that dysregulated epithelial-ILC2 circuits in the respiratory tract, including nasopharynx (NP), trachea and airways, underlie the presence of persistent niches where allergic pathology is sustained. Using novel genetic tools in mice that permit exquisite dissection of such circuits, we propose 3 Specific Aims that align within the overall goals of the PPG. First, we will define the ILC2 landscape in mouse skin, NP, trachea and lung, where we have uncovered unsuspected diversity that has already been extended to human studies by others in the PPG. Second, we will define the tuft cell landscape in NP and trachea, since the critical role for this enigmatic epithelial cell was uncovered in our intestinal studies. We have demonstrated tuft cell hyperplasia in human allergic polyps. Third, we will use a mouse model of skin inflammation followed by lung allergen challenge to analyze the development of the epithelial-ILC2 circuit from skin to NP to lung, and the role of these respective cells. These findings will be applied to human tissues collected in Core B of this PPG and analyzed in Core C of this PPG to generate discovery in patients with severe asthma. Together, this PPG will uncover dysfunctional cellular networks and niches that sustain allergic immunopathology in the lung.