Regulation of tissue resident macrophage development by IL-7R signaling

IL-7R 信号传导调节组织驻留巨噬细胞发育

• 批准号: 9883828
• 负责人: Anna E. Beaudin
• 金额: $ 37.32万
• 依托单位: UNIVERSITY OF CALIFORNIA, MERCED
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2020-03-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9883828
• 关键词: Activities of Daily Living; Address; Adoptive Transfer; Adult; Automobile Driving; Blood; Cell physiology; Cells; Characteristics; Cues; Cytokine Receptors; Data; Development; Developmental Process; Disease; Epidermis; Fetal Development; Fetal Liver; Fetal Tissues; Genetic Transcription; Goals; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Homeostasis; IL7 gene; IL7R gene; Immune; Immunity; Immunologic Surveillance; Impairment; Interleukin 7 Receptor; Interleukin-7; Investigation; Knowledge; Label; Longevity; Lung; Lymphocyte; Lymphoid; Maintenance; Molecular; Mus; Myelogenous; Myeloid Cells; Natural regeneration; Nature; Normal tissue morphology; Pathogenesis; Pathway interactions; Pregnancy; Process; Production; Property; Receptor Signaling; Recording of previous events; Regulation; Research Project Grants; Role; Shapes; Signal Pathway; Signal Transduction; Specific qualifier value; Surface; Time; Tissues; Transducers; Work; brain tissue; experimental study; fetal; genetic approach; immune function; insight; macrophage; monocyte; novel; progenitor; protein expression; receptor; self-renewal

The recent discovery that adult hematopoietic (blood) stem cells (HSCs) do not produce all immune cells despite sustaining blood production across the lifespan has fundamentally challenged our understanding of both immune development and function. Adoptive transfer studies and fate mapping experiments have demonstrated that tissue-resident macrophages are only specified during fetal development and cannot be generated or regenerated in adulthood. As compared to their adult HSC-derived counterparts, fetal-derived tissue resident macrophages reside and self-renew within their resident tissues, where they perform distinct homeostatic and immune surveillance functions. The discovery of a fetal origin of tissue-resident macrophages has raised many new questions about their specification, persistence across the lifespan, and distinct function. The long-term objective of this proposal is to define the developmental mechanisms underlying the unique functional capacity of tissue resident macrophages across the lifespan in order to illuminate their distinct role in both adult tissue homeostasis and disease. Recent work in our lab has identified interleukin-7 receptor (IL-7R) signaling as a novel mechanism regulating the establishment of tissue resident macrophages during fetal development. IL-7R signaling is restricted to regulation of the lymphoid lineage in adult hematopoiesis. The reliance of fetal myeloid specification on IL-7R signaling suggests that fetal hematopoiesis exploits alternate differentiation pathways in order to confer distinct characteristics on fetal-derived macrophages. In this proposal, we will capitalize on the discovery of this new regulatory mechanism to dig deeper into how these distinct immune cells are specified from fetal precursors during development. In Aim 1, we will use genetic approaches to determine the requirement for IL7R signaling during fetal myeloid specification. We will specifically delete the receptor sub-chain IL7raain a range of progenitors and mature cells at different stages of development to define how IL7rα regulates myeloid specification during fetal development. In Aim 2, we will define for the first time how IL-7R signaling occurs in myeloid cells - including downstream signal transducers and transcriptional targets- and the specific developmental processes that are regulated by IL-7R signaling during fetal macrophage establishment. In Aim 3, we will establish the function of IL-7 as a fetal myeloid niche factor and define both the requirement for IL-7 and which cell subsets are responsible for producing IL-7 within resident tissues to support macrophage development. Together, work from the proposed studies will illuminate how alternative differentiation pathways during fetal hematopoiesis impart distinct functional characteristics on fetal-derived tissue resident macrophages, and thereby illuminate the role of specific ontogenetic subsets of macrophages in normal tissue and disease processes.

最近发现成人造血干细胞(HSCs)并不能产生所有的免疫细胞 尽管在整个生命周期内维持血液生产从根本上挑战了我们对 包括免疫发育和免疫功能。采用迁移研究和命运映射实验 证明组织驻留的巨噬细胞只在胎儿发育过程中被指定，不能 成年的成年后产生或再生的与成年HSC来源的同龄人相比，胎儿来源的 组织驻留巨噬细胞驻留并在其驻留组织内自我更新，在那里它们执行不同的 动态平衡和免疫监视功能。组织驻留巨噬细胞起源于胎儿的发现 对它们的规范、在整个生命周期中的持久性和独特的功能提出了许多新的问题。 这项提议的长期目标是定义独特的 组织驻留巨噬细胞在整个寿命中的功能能力，以阐明它们在 成人组织的动态平衡和疾病。我们实验室最近的工作发现了白细胞介素7受体(IL-7R) 信号作为一种新的机制调节胎儿组织驻留巨噬细胞的建立 发展。IL-7R信号仅限于成人造血中淋巴系的调节。这个 胎儿髓系对IL-7R信号的依赖提示胎儿造血利用替代 分化途径，以赋予胎儿来源的巨噬细胞不同的特征。在这 提议，我们将利用这一新的监管机制的发现，更深入地挖掘这些 在发育过程中，不同的免疫细胞是从胎儿前体细胞中特定出来的。在目标1中，我们将使用基因 在胎儿髓系规范过程中确定IL7R信号需求的方法。我们会 具体地，删除受体亚链IL7来自一系列处于不同阶段的祖细胞和成熟细胞 研究进展以确定IL7rα如何在胎儿发育过程中调节髓系规格。在目标2中，我们将 首次确定IL-7R信号如何在髓系细胞中发生--包括下游信号转导 和转录靶点--以及受IL-7R信号调控的特定发育过程 在胎儿巨噬细胞建立过程中。在目标3中，我们将建立IL-7作为胎儿髓系利基的功能 因子和定义对IL-7的需求以及哪些细胞亚群负责在 支持巨噬细胞发育的常驻组织。总之，来自拟议研究的工作将阐明 胎儿造血过程中不同的分化途径如何赋予细胞不同的功能特征 胎儿来源的组织驻留巨噬细胞，从而阐明特定的个体发育亚群在 正常组织和疾病过程中的巨噬细胞。