Metabolic imprinting of dendritic cell fate and function in tissues

组织中树突状细胞命运和功能的代谢印记

• 批准号: 10580181
• 负责人: BALI PULENDRAN
• 金额: $ 11.83万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580181
• 关键词: ATAC-seq; Adoptive Transfer; Allergic; Allergic inflammation; Alveolar Macrophages; Amino Acids; Autophagocytosis; Bone Marrow; Cell physiology; Cells; Cellular biology; Chimera organism; Data; Dendritic Cells; Development; EIF4EBP1 gene; Epigenetic Process; Epithelial Cells; FRAP1 gene; Genetic Transcription; Genetic Translation; Hematopoietic; Homeostasis; ITGAM gene; ITGAX gene; Immune response; Immunity; In Situ; Infection; Inflammasome; Inflammation; Knockout Mice; Lung; Lymphoid Cell; Mediating; Metabolic; Modeling; Molecular; Mus; Natural Killer Cells; Nature; Organ; Outcome; Pathway interactions; Phenotype; Play; Raptors; Role; Signal Pathway; Signal Transduction; Spleen; Starvation; Stimulus; Stress; Tissues; Vaccination; Viral; Work; adaptive immunity; cell type; conditional knockout; functional plasticity; gene repression; gut inflammation; imprint; insight; lipid metabolism; mTOR Signaling Pathway; macrophage; metabolic profile; microbial; monocyte; neutrophil; pathogen; programs; pulmonary function; receptor; response; sensor; transcription factor

ABSTRACT Dendritic cells (DCs) play a central role in sensing pathogens and tuning immune responses. Functionally distinct subsets of DCs can stimulate different types of immune responses, but DCs also display functional plasticity in response to microbial stimuli or signals from the tissue microenvironment. However, it is now clear that DCs sense not just microbial stimuli, but also various stress signals (e.g. amino acid starvation), through ancient stress sensing mechanisms, leading to a metabolic reprogramming of their function. In particular our recent work has revealed fundamental roles for two major amino acid sensors GCN2 and mTOR, in programming DCs to modulate adaptive immunity and inflammation. We have shown that GCN2 plays a role in programming DCs to respond to viral vaccination, and in controlling intestinal inflammation by promoting autophagy and suppressing inflammasome activation in gut APCs and epithelial cells. Furthermore, our recent data demonstrates that GCN2 regulates allergic inflammation in the lung. In addition to these effects of GCN2, we have recently shown that mTOR regulates developmental fate of DCs and alveolar macrophages (AMs) in the lung, and reprograms their metabolic state to modulate the outcome of allergic inflammation. In the following aims, we will determine the mechanisms of this metabolic imprinting. Aim 1: To determine the mechanisms by which mTOR controls the homeostasis and function of lung DCs and AMs in the steady state and during allergic inflammation. Our recent work demonstrates that in mice in which mTOR is genetically ablated in CD11c+ cells (mTORAPC mice): (i) CD103+ DCs and AMs in the lung are greatly reduced in number, in the steady state. (ii) Although the lung CD11c+CD11b+ DCs were numerically unaffected, they were skewed in their transcriptional identity towards the macrophage/monocytic profile. (iii) Lung allergic Th2 inflammation was skewed toward the Th17/neutrophilic phenotype. In the present aim, we will investigate the mechanisms underlying these effects, and investigate the potential role of 4E-BP3 dependent translational control, lipid metabolism and epigenetic reprograming in mediating the effects of mTOR signaling. Aim 2: To determine the mechanisms by which GCN2 regulates Th2 responses and allergic inflammation. Our preliminary data demonstrate that GCN2 knockout mice display markedly reduced allergic inflammation in the lung. In this aim we will determine the molecular mechanisms underlying this effect. The successful completion of these aims will yield rich mechanistic insights about metabolic imprinting of DC fate and function.

抽象的 树突状细胞（DC）在传感病原体和调整免疫反应中起着核心作用。 DC的功能不同的子集可以刺激不同类型的免疫反应，但DCS 还显示出对微生物刺激或组织信号的功能可塑性 微环境。但是，现在很明显，DCS不仅感觉到微生物刺激，还感知 各种应力信号（例如氨基酸饥饿），通过古老的压力感应机制， 导致其功能的代谢重编程。特别是我们最近的工作 揭示了两个主要氨基酸传感器GCN2和MTOR的基本作用， 编程DC来调节适应性免疫和炎症。我们已经证明了GCN2 在编程DC中发挥作用，以应对病毒疫苗接种并控制肠道 通过促进自噬和抑制肠道APC的炎症来炎症 和上皮细胞。此外，我们最近的数据表明GCN2调节过敏性 肺部炎症。除了GCN2的这些影响外，我们最近还表明 MTOR调节肺中DC和肺泡巨噬细胞（AMS）的发育命运，并且 重新编程其代谢状态以调节过敏性炎症的结果。在 以下目的，我们将确定这种代谢印迹的机制。 目标1：确定mTOR控制体内平衡的机制和 肺直流和AM的功能在稳态和过敏性炎症期间的功能。我们的 最近的工作表明，在CD11C+细胞中MTOR遗传烧蚀的小鼠中 （MTORAPC小鼠）：（i）肺中的CD103+ DC和AMS的数量大大减少 稳定状态。 （ii）尽管肺CD11C+ CD11b+ DC在数值上不受影响，但它们是 在其转录身份偏向巨噬细胞/单核细胞谱。 （iii）肺 过敏性TH2炎症偏向Th17/中性粒细胞表型。现在 目的，我们将研究这些作用的基础机制，并研究潜力 4E-BP3依赖的翻译控制，脂质代谢和表观遗传重编程的作用 介导MTOR信号的影响。 目标2：确定GCN2调节Th2响应的机制和 过敏性炎症。我们的初步数据表明GCN2敲除小鼠显示 明显减少了肺部过敏性炎症。在此目标中，我们将确定分子 这种效果的基础机制。这些目标的成功完成将产生富裕 关于直流命运和功能的代谢印迹的机械见解。