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.

项目摘要/摘要 蠕虫，过敏原和某些生物均刺激2型免疫反应，并显着贡献 全球疾病负担。目前，全世界有超过10亿个人感染了蠕虫， 过敏性疾病的发生率上升代表了一种新兴的流行病。感应和信号事件 该启动2型免疫力仍然很少理解，但是在小肠中，它们需要上皮簇细胞。 簇簇细胞调节塔夫特 - ilc2电路，其中簇细胞衍生的IL-25激活了第2组先天淋巴样细胞 （ILC2S）在基础组织中。 ILC2S分泌规范的2型细胞因子IL -5，-9和-13，它 共同驱动2型免疫力的标志，例如嗜酸性粒细胞和组织重塑。 IL-13也是如此 通过诱导簇簇和杯状细胞增生来促进前馈反应。簇的免疫功能 细胞需要化学感应途径，最近的研究确定了微生物代谢物琥珀酸酯为 足以激活Tuft-ILC2电路的肠道簇状细胞配体。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子函数：（1）簇细胞构成表达IL-25，但饲料向前 Tuft-ILC2电路仅在有蠕虫或生物的存在下激活 信号； （2）发生免疫传感后簇簇细胞增生的启动表明簇细胞 有助于2型免疫的效应子阶段； （3）在簇细胞中，蠕虫清除更延迟 缺乏仅缺乏IL-25的小鼠的小鼠。因此，该建议的目的是发现和 表征小肠中新型的簇状细胞效应子的功能。使用创新的体外结合 测定和体内蠕虫感染了转基因小鼠菌株，我们建议测试调节 簇衍生的IL-25，白三烯C4和乙酰胆碱的功能。这些研究应该确定新颖 在蠕虫感染和过敏性疾病中进行治疗干预的靶标。