Regulation of Gut Innate Lymphoid Cells by Ahr

Ahr 对肠道先天淋巴细胞的调节

• 批准号: 9361647
• 负责人: Liang Zhou
• 金额: $ 53.43万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9361647
• 关键词: Allergic Disease; Aryl Hydrocarbon Receptor; Autoimmunity; Cell Differentiation process; Cell physiology; Cells; Cellular biology; Chromatin; Colitis; Data; Development; Diet; Dietary Component; Disease; Dose; Enteral; Environment; Environmental Impact; Environmental Risk Factor; Epithelial; Epithelial Cells; Equilibrium; Exhibits; Family; Fatty acid glycerol esters; GATA3 gene; Gene Expression Profile; Genetic; Genetic Transcription; Germ-Free; Human; Immune; Immunity; Infection; Inflammation; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Injury; Interleukin-13; Interleukin-5; Intestines; Ligands; Lung; Lymphoid Cell; Maintenance; Mediating; Microbe; Modeling; Molecular; Molecular Mechanisms of Action; Mucous Membrane; Mus; Natural Killer Cells; Pathogenesis; Pathway interactions; Physiological; Play; Prevention; Production; Receptor Activation; Regulation; Reporter; Role; Sodium Dextran Sulfate; Stimulus; Symbiosis; Testing; Tissues; Toxic Environmental Substances; Transcriptional Regulation; Xenobiotics; base; cell type; cytokine; experimental study; gut microbiota; human disease; insight; microbial; microbiota; novel; novel therapeutics; pathogen; receptor; receptor expression; response; sensor; small molecule; tool; transcription factor; transcriptome

Project Summary/Abstract: Innate lymphoid cells (ILCs) represent an emerging family of cell types that express signature transcription factors, including T-bet+ Eomes+ natural killer (NK) cells, T-bet+ Eomes– type 1 ILCs (ILC1), Gata3+ type 2 ILCs (ILC2), and RORgt+ type 3 ILCs (ILC3). ILCs are abundantly present in mucosal tissues (e.g., lung and gut) at the interface of host-environment interactions. ILC1, ILC2, and ILC3 can readily respond to external stimuli (microbes or dietary components) and produce effector cytokines that mirror their adaptive immune counterparts, Th1, Th2, and Th17/22 cells, respectively. Molecular mechanisms underlying the development and function of ILCs are poorly understood. The aryl hydrocarbon receptor (Ahr) is a ligand-dependent transcription factor, best known to mediate the effects of xenobiotic environmental toxins and endogenous microbial and dietary metabolites. We and others have shown that Ahr is required for ILC3 maintenance and function. Our preliminary data revealed tissue-specific expression of Ahr in ILCs and differential regulation of ILC differentiation and function by Ahr in the gut. We hypothesize that Ahr regulates the ILC2-ILC3 balance in the gut, thus impacting intestinal inflammation and immunity. Specifically, we will investigate 1) the regulation of Ahr expression in ILCs, 2) the molecular mechanism(s) by which Ahr regulates the ILC2-ILC3 balance in the gut, and 3) the functional role of Ahr in regulation of ILCs in DSS-induced gut injury. These experiments will offer an opportunity to elucidate environmental impacts on gut inflammation and immunity via the Ahr-mediated pathway. Our study will provide novel cellular and molecular insights into the development and function of ILCs regulated by Ahr in a tissue- and cell-specific manner. Since Ahr is a ligand-dependent transcription factor and its activity can be regulated by small molecules, modulating Ahr expression and/or function in ILCs may represent a new paradigm for human disease treatment or prevention (e.g., inflammatory bowel disease, enteric infections, and allergic diseases).

项目概要/摘要： 先天性淋巴样细胞（ILC）代表了一个新兴的家族的细胞类型，表达的签名转录 因子，包括T-bet+ Eomes+自然杀伤（NK）细胞、T-bet+ Eomes-1型ILC（ILC 1）、Gata 3 + 2型ILC （ILC 2）和RORgt+3型ILC（ILC 3）。ILC大量存在于粘膜组织（例如，肺和肠）. 宿主与环境交互的界面。ILC 1、ILC 2和ILC 3可以容易地响应外部刺激 （微生物或饮食成分）并产生反映其适应性免疫的效应细胞因子 Th 1、Th 2和Th 17/22细胞。发展的分子机制 ILC的功能和功能知之甚少。芳香烃受体（Ahr）是一种配体依赖性受体， 转录因子，最为人所知的是介导外源性环境毒素和内源性 微生物和饮食代谢物。我们和其他人已经表明，Ahr是ILC 3维护所必需的， 功能我们的初步数据揭示了ILC中Ahr的组织特异性表达以及Ahr的差异调节 ILC在肠道中通过Ahr的分化和功能。我们假设Ahr调节ILC 2-ILC 3平衡， 肠道，从而影响肠道炎症和免疫力。具体来说，我们将研究1）监管 2）Ahr调节ILC 2-ILC 3平衡的分子机制， 3）Ahr在DSS诱导的肠损伤中调节ILC的功能作用。这些实验将 提供了一个机会，阐明环境对肠道炎症和免疫的影响，通过Ahr介导的 通路我们的研究将为ILC的发育和功能提供新的细胞和分子见解 由Ahr以组织和细胞特异性方式调节。由于Ahr是配体依赖性转录因子， 其活性可由小分子调节，调节ILC中Ahr表达和/或功能可 代表人类疾病治疗或预防的新范例（例如，炎症性肠病， 肠道感染和过敏性疾病）。