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: 10574553
• 负责人: Anna E. Beaudin
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF UTAH
• 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10574553
• 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; Investigation; Knowledge; Label; Longevity; Lung; Lymphocyte; Lymphoid; Macrophage; Maintenance; Maps; 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; monocyte; novel; progenitor; protein expression; receptor; self-renewal; stem cells

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（血液）干细胞（HSC）不能产生所有免疫细胞 尽管在整个生命周期中维持血液生产从根本上挑战了我们对 免疫发育和功能。过继转移研究和命运图谱实验已经 证明组织驻留巨噬细胞仅在胎儿发育期间被指定，并且不能被指定 成年后产生或再生。与成人 HSC 衍生的对应物相比，胎儿衍生的 HSC 组织驻留巨噬细胞在其驻留组织内驻留并自我更新，在那里它们执行不同的任务 稳态和免疫监视功能。组织驻留巨噬细胞的胎儿起源的发现 提出了许多关于其规格、整个生命周期的持久性和独特功能的新问题。 该提案的长期目标是定义独特的发展机制 组织驻留巨噬细胞在整个生命周期中的功能能力，以阐明它们在 成人组织稳态和疾病。我们实验室最近的工作已鉴定出白细胞介素 7 受体 (IL-7R) 信号传导作为调节胎儿期组织驻留巨噬细胞建立的新机制 发展。 IL-7R 信号传导仅限于成人造血过程中淋巴谱系的调节。这 胎儿骨髓规范对 IL-7R 信号传导的依赖表明胎儿造血利用交替 分化途径，以便赋予胎儿源性巨噬细胞独特的特征。在这个 提案中，我们将利用这一新监管机制的发现，更深入地研究这些机制如何 不同的免疫细胞是在发育过程中从胎儿前体中特异出来的。在目标 1 中，我们将使用遗传 确定胎儿骨髓规范期间对 IL7R 信号传导的需求的方法。我们将 特异性删除一系列处于不同阶段的祖细胞和成熟细胞中的受体子链IL7raa 发育来定义 IL7rα 在胎儿发育过程中如何调节骨髓规范。在目标 2 中，我们将 首次定义了骨髓细胞中 IL-7R 信号传导的发生方式 - 包括下游信号转导器 和转录靶点 - 以及受 IL-7R 信号传导调节的特定发育过程 在胎儿巨噬细胞建立期间。在目标 3 中，我们将建立 IL-7 作为胎儿骨髓生态位的功能 因素并定义对 IL-7 的需求以及哪些细胞亚群负责产生 IL-7 支持巨噬细胞发育的常驻组织。拟议的研究工作将共同阐明 胎儿造血过程中的替代分化途径如何赋予不同的功能特征 胎儿来源的组织常驻巨噬细胞，从而阐明特定个体发育子集的作用 正常组织和疾病过程中的巨噬细胞。