Tuft cell effector functions in the small intestine

簇细胞效应器在小肠中发挥作用

• 批准号: 10343684
• 负责人: Jakob H. von Moltke
• 金额: $ 55.96万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10343684
• 关键词: Acetylcholine; Allergens; Allergic Disease; Attention; Biological Assay; Cells; Cellular Morphology; Effector Cell; Electron Microscopy; Eosinophilia; Epidemic; Epithelial; Event; Frequencies; Funding; Gene Expression Profile; Gene Expression Profiling; Goals; Goblet Cells; Health; Helminths; Human; Hyperplasia; Hypersensitivity; Immune; Immune response; Immunity; Immunology; In Vitro; Incidence; Individual; Infection; Inflammation; Interleukin-13; Interleukin-5; Intestines; Ions; Laboratories; Leukotriene C4; Leukotrienes; Ligands; Link; Lipids; Liquid substance; Lung; Lymphoid Cell; Measures; Membrane; Modeling; Mouse Strains; Mucous body substance; Mus; Neuromedin U; Neuropeptides; Pathway interactions; Peptides; Physiology; Positioning Attribute; Prevalence; Production; Publishing; Reagent; Regulation; Role; Sentinel; Signal Transduction; Small Intestines; Stimulus; Succinates; Testing; Therapeutic Intervention; Tissues; Transcription Factor AP-1; Transgenic Mice; Work; base; burden of illness; cell type; cytokine; experimental study; helminth infection; immune function; in vitro Assay; in vivo; innovation; microbial; mouse model; new therapeutic target; novel; paracrine; release of sequestered calcium ion into cytoplasm; response; skills; tool

Project Summary/Abstract Helminths, allergens, and certain protists all stimulate a type 2 immune response and contribute significantly to the global disease burden. Currently, more than 1 billion individuals worldwide are infected with helminths, and the rising incidence of allergic disease represents an emerging epidemic. The sensing and signaling events that initiate type 2 immunity remain poorly understood, but in the small intestine they require epithelial tuft cells. Tuft cells regulate a tuft-ILC2 circuit in which tuft cell-derived IL-25 activates group 2 innate lymphoid cells (ILC2s) in the underlying tissue. ILC2s secrete the canonical type 2 cytokines IL-5, -9, and -13, which collectively drive hallmarks of type 2 immunity, such as eosinophilia and tissue remodeling. IL-13 also promotes a feed-forward response by inducing tuft and goblet cell hyperplasia. The immune function of tuft cells requires a chemosensory pathway and recent studies identified the microbial metabolite succinate as an intestinal tuft cell ligand that is sufficient to activate the tuft-ILC2 circuit. Tuft cells therefore act as IL-25- secreting immune sentinels, but several lines of evidence support the central hypothesis of this proposal that additional tuft cell effector functions must exist: (1) Tuft cells express IL-25 constitutively, but the feed-forward tuft-ILC2 circuit is only activated in the presence of helminths or protists, suggesting additional activating signals; (2) the initiation of tuft cell hyperplasia after immune sensing has occurred suggests tuft cells contribute to the effector stages of type 2 immunity; and (3) helminth clearance is more delayed in tuft cell- deficient mice than in mice that lack only IL-25. The goal of this proposal is therefore to discover and characterize novel tuft cell effector functions in the small intestine. Using a combination of innovative in vitro assays and in vivo helminth infection of genetically modified mouse strains, we propose to test the regulation and function of tuft cell-derived IL-25, leukotriene C4, and acetylcholine. These studies should identify novel targets for therapeutic intervention in both helminth infection and allergic disease.

项目概要/摘要 蠕虫、过敏原和某些原生生物都会刺激 2 型免疫反应，并显着促进 全球疾病负担。目前，全球有超过 10 亿人感染蠕虫， 过敏性疾病发病率的上升代表着一种新出现的流行病。传感和信号事件 启动 2 型免疫的机制仍知之甚少，但在小肠中它们需要上皮簇细胞。 簇细胞调节簇-ILC2 回路，其中簇细胞衍生的 IL-25 激活第 2 组先天淋巴细胞 （ILC2）位于下层组织中。 ILC2 分泌典型的 2 型细胞因子 IL-5、-9 和 -13， 共同驱动 2 型免疫的标志，例如嗜酸性粒细胞增多和组织重塑。 IL-13 也 通过诱导簇细胞和杯状细胞增生来促进前馈反应。毛簇的免疫功能 细胞需要化学感应途径，最近的研究发现微生物代谢物琥珀酸是一种化学感应途径。 足以激活 tuft-ILC2 回路的肠簇细胞配体。因此簇细胞充当 IL-25- 分泌免疫哨兵，但有几条证据支持该提议的中心假设： 必须存在额外的簇细胞效应功能：(1) 簇细胞组成型表达 IL-25，但前馈 tuft-ILC2 电路仅在存在蠕虫或原生生物的情况下才会被激活，这表明需要额外的激活 信号； (2) 免疫感应发生后簇细胞增生的开始表明簇细胞 有助于2型免疫的效应阶段； (3) 簇细胞中蠕虫的清除更加延迟- 缺陷小鼠与仅缺乏 IL-25 的小鼠相比。因此，本提案的目标是发现并 表征小肠中新型簇细胞效应功能。使用创新的体外组合 转基因小鼠品系的测定和体内蠕虫感染，我们建议测试调节 以及簇细胞衍生的 IL-25、白三烯 C4 和乙酰胆碱的功能。这些研究应该确定新颖的 蠕虫感染和过敏性疾病治疗干预的目标。