Amino acid availability acts as a critical environmental rheostat of mucosal ILC2 responses

氨基酸可用性是粘膜 ILC2 反应的关键环境变阻器

• 批准号: BB/T014482/1
• 负责人: Matthew Hepworth
• 金额: $ 61.46万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FT014482%2F1
• 关键词: Amino; acid; availability; acts; critical

Our intestines are continually exposed to a wide range of stimuli from the environment in the form of bacteria - both beneficial and harmful - and metabolically active molecules released during the digestion of food. The immune system continually acts to keep the intestine healthy and functioning normally, and to prevent any damage caused by infections or chemicals entering the body during feeding. Recent advances have shown that the balance of bacterial and dietary-derived signals in the intestine dramatically alters the way the immune system responds, and changes in this balance can result in reduced immunity to infection, inflammation or even the progression of obesity or cancer. However, the precise nature of these environmental signals and the way immune cells respond to them remains unclear, blocking the development of new treatments aimed at modifying environmental signals in the gut, or targeting the immune cell sensors that detect them.In this project we will build upon new and exciting early work in our lab that suggest that a population of tissue-resident innate immune cells continually sense the intestinal environment for changes in a family of so-called "essential" amino acids. These amino acids are critical to keep us healthy but cannot be made by human cells and must be ingested from digestion of food in the diet. This particular population of gut-resident immune cells constantly surveys the intestine for potential danger, and responds quickly in response to danger or infections to launch protective immunity and to repair the tissue. The speed of this response is highly reliant on the ability to sense changes in the gut environment, as well as the cells ability to import basic building blocks of proteins - in the form of amino acids - that act to "fuel" immune function. We show these cells have a much higher ability to sense changes in intestinal amino acid levels compared to other immune cells, which allows them to generate an appropriate fast and powerful immune response. In this proposal we suggest that the ability of these immune cells to sense essential amino acids is critical for the intestinal immune system to sense infections or potential danger.We propose to further explore this hypothesis using exciting, new experimental tools and approaches which will allow us to determine exactly how these critical immune cells respond to changes in amino acids in the intestinal environment. In particular, we have identified two key genes that encode for amino acid "transporters" that detect and take up amino acids into immune cells. Using models in which these genes have been deleted within immune cells we have generated early findings which suggest the levels of amino acids both outside and inside an immune cell determine the degree to which that cell can perform it's tissue protective functions and respond to intestinal infection.Our central objectives are to utilize new technologies and experimental tools in the lab to better understand how immune cells sense their environment - particularly how they respond to changes in important nutrients and metabolites to ensure appropriate responses that subsequently keep our intestines healthy. These findings could have important consequences for a wide range of intestinal diseases by helping us to understand how environment risk factors such as diet and infections alter the function of the immune system and determine intestinal health.

我们的肠道不断以细菌形式暴露于环境中的广泛刺激（既有益和有害），并且在食物消化过程中释放出代谢活性分子。免疫系统不断起作用，以使肠道保持健康和正常功能，并防止在喂养过程中因感染或化学物质而造成的任何损害。最近的进步表明，在肠道中细菌和饮食来源的信号平衡显着改变了免疫系统的反应方式，这种平衡的变化可能导致对感染，炎症甚至肥胖或癌症进展的免疫力降低。然而，这些环境信号的精确性质和免疫细胞对它们的反应方式仍然不清楚，阻止了旨在修改肠道中环境信号的新处理的发展，或者针对肠道中的环境信号，或者针对检测到它们的免疫细胞传感器。我们将在我们的实验室中建立新的和令人兴奋的早期工作，这些工作在我们实验室中建立了艰苦的环境，以使居民的整体环境变得更加艰难，从而改变了本质上的范围。酸。这些氨基酸对于保持我们的健康至关重要，但不能被人类细胞制成，必须从饮食中食物消化中摄入。这种特殊的肠道居民免疫细胞不断调查肠子是否有潜在的危险，并迅速反应危险或感染以发射保护性免疫和修复组织。这种反应的速度高度依赖于感知肠道环境变化的能力，以及细胞以氨基酸的形式导入蛋白质基本构建基础的能力，这些蛋白质可用于“燃料”免疫功能。我们显示，与其他免疫细胞相比，这些细胞具有更高的肠道氨基酸水平变化的能力，这使它们能够产生适当的快速和强大的免疫反应。在该提案中，我们建议这些免疫细胞感知必需氨基酸的能力对于肠道免疫系统感染或潜在危险至关重要。我们建议使用令人兴奋的，新的实验工具和方法进一步探索这一假设，这将使我们确切地确定这些关键的这些关键的免疫细胞在肠道环境中对氨基酸的变化反应。特别是，我们已经确定了两个编码氨基酸“转运蛋白”的关键基因，它们检测并将氨基酸吸收到免疫细胞中。 Using models in which these genes have been deleted within immune cells we have generated early findings which suggest the levels of amino acids both outside and inside an immune cell determine the degree to which that cell can perform it's tissue protective functions and respond to intestinal infection.Our central objectives are to utilize new technologies and experimental tools in the lab to better understand how immune cells sense their environment - particularly how they respond to changes in important nutrients and metabolites to ensure appropriate responses随后，我们的肠道保持健康。通过帮助我们了解饮食和感染等环境风险因素如何改变免疫系统的功能并确定肠道健康，这些发现可能会对多种肠道疾病产生重要影响。

项目成果

Bcl-2 supports survival and metabolic fitness of quiescent tissue-resident ILC3.

• DOI: 10.1016/j.mucimm.2023.07.001
• 发表时间: 2023-10
• 期刊: MUCOSAL IMMUNOLOGY
• 影响因子: 8
• 作者: King, James I.;Melo-Gonzalez, Felipe;Malengier-Devlies, Bert;Tacho-Pinot, Roser;Magalhaes, Marlene S.;Hodge, Suzanne H.;Ros, Xavier Romero;Gentek, Rebecca;Hepworth, Matthew R.
• 通讯作者: Hepworth, Matthew R.

Regulation of systemic metabolism by tissue-resident immune cell circuits.

• DOI: 10.1016/j.immuni.2023.05.001
• 发表时间: 2023-06
• 期刊: Immunity
• 影响因子: 32.4
• 作者: Joey H. Li;M. Hepworth;Timothy E. O’Sullivan

Amino acid availability acts as a metabolic rheostat to determine the magnitude of ILC2 responses.

• DOI: 10.1084/jem.20221073
• 发表时间: 2023-03-06
• 期刊: The Journal of experimental medicine

Rhythmicity of intestinal IgA responses confers oscillatory commensal microbiota mutualism.

• DOI: 10.1126/sciimmunol.abk2541
• 发表时间: 2022-09-02
• 期刊: Science immunology
• 影响因子: 24.8
• 作者: Penny HA;Domingues RG;Krauss MZ;Melo-Gonzalez F;Lawson MAE;Dickson S;Parkinson J;Hurry M;Purse C;Jegham E;Godinho-Silva C;Rendas M;Veiga-Fernandes H;Bechtold DA;Grencis RK;Toellner KM;Waisman A;Swann JR;Gibbs JE;Hepworth MR
• 通讯作者: Hepworth MR

Group 2 Innate Lymphoid Cells Are Detrimental to the Control of Infection with Francisella tularensis.

• DOI: 10.4049/jimmunol.2100651
• 发表时间: 2023-03-01
• 期刊: JOURNAL OF IMMUNOLOGY
• 影响因子: 4.4
• 作者: Dow, Joshua;Cytlak, Urszula M.;Casulli, Joshua;McEntee, Craig P.;Smedley, Catherine;Hodge, Suzanne H.;D'Elia, Riccardo, V;Hepworth, Matthew R.;Travis, Mark A.
• 通讯作者: Travis, Mark A.