Endothelial Instruction of Macrophage Fate in Inflammatory Lung Injury

炎症性肺损伤中巨噬细胞命运的内皮指令

• 批准号: 10701931
• 负责人: Jalees Rehman
• 金额: $ 42.8万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701931
• 关键词: ATP Citrate (pro-S)-Lyase; Acetyl Coenzyme A; Acute Lung Injury; Adult; Alveolar Macrophages; Anti-Inflammatory Agents; Binding; Blood Vessels; Cell Line; Cell Nucleus; Cells; Characteristics; Collaborations; Complex; Data; Endothelial Cells; Endothelium; Enzymes; Epigenetic Process; G-Protein-Coupled Receptors; Generations; Genetic Transcription; Histone Acetylation; Homeostasis; Human; ITGAM gene; Image; Immune; In Vitro; Individual; Inflammation; Inflammatory; Injury; Instruction; Leucine-Rich Repeat; Licensing; Life; Lipoprotein Receptor; LoxP-flanked allele; Lung; Macrophage; Measures; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Modification; Mus; NADH; Patients; Phenotype; Population; Process; Proteins; Regulation; Resolution; Respiration; Role; Signal Transduction; Testing; Tissues; Transcription Coactivator; Transcriptional Activation; Transcriptional Regulation; WNT Signaling Pathway; beta catenin; cell type; cofactor; epigenetic regulation; epigenome; high resolution imaging; in vivo; interstitial; lung injury; metabolomics; migration; mitochondrial metabolism; monocyte; mouse model; optogenetics; prenatal; programs; receptor; response to injury; single-cell RNA sequencing; synthetic biology; tissue injury; tissue repair; transcriptomics

PROJECT SUMMARY/ABSTRACT Studies have shown much broader roles for macrophages in responding to inflammation and tissue injury than previously recognized, such as promoting inflammation resolution, tissue repair and restoring tissue homeostasis and this recognition of macrophage plasticity has shifted the focus away from the simple notion of M1 and M2 dichotomies. Project 3 focuses on delineating the signals mediating monocyte transition to tissue macrophages and their potentially essential role in tissue repair in acute lung injury (ALI). As the lung endothelium is the entry point of the monocytes transmigrating into tissue, endothelial cells (ECs) may modify the downstream macrophage phenotype, and thus the interaction between cells may be of great consequence. Project 3 will delineate mechanisms of generation of how ECs instruct macrophages and their role in resolving ALI. We will address fundamental questions including: What are the EC signals mediating transition to the reparative macrophage populations? What signals in macrophages in turn convert the cells to repair tissue? What are the epigenetic and transcriptomic features of these phenotype-shifted macrophages? In Project 3 we will test the hypothesis that the lung endothelium via Wnt signaling mediates macrophage phenotype transition through modifying mitochondrial metabolism and epigenome that initiates specific transcriptional programs. In Aim 1, we will define the role of endothelial Wnt signaling in regulating the differentiation of monocytes to macrophages in lungs. Here we will determine the role of the Wnt signaling regulator Rspondin 3 (Rspo3) derived from ECs in signaling the transition of monocytes to lung macrophages. In Aim 2, we will determine the role of metabolic reprogramming and epigenetic modifications of macrophages in mediating phenotype transition and thereby reducing the extent of lung injury as well as promoting its resolution.

项目总结/摘要 研究表明，巨噬细胞在响应炎症和组织损伤中的作用比 如促进炎症消退、组织修复和恢复组织稳态 这种对巨噬细胞可塑性的认识已经将焦点从M1和M2的简单概念转移到了 二分法项目3的重点是描绘介导单核细胞向组织巨噬细胞转化的信号， 它们在急性肺损伤（ALI）的组织修复中的潜在重要作用。由于肺内皮细胞是 当单核细胞迁移到组织中时，内皮细胞（EC）可以修饰下游的巨噬细胞， 表型，因此细胞之间的相互作用可能是重要的结果。项目3将描述 EC如何指导巨噬细胞的产生机制及其在解决ALI中的作用。我们将解决 基本问题包括：什么是EC信号介导的过渡到修复性巨噬细胞 人口？巨噬细胞中的什么信号反过来将细胞转化为修复组织？什么是表观遗传和 这些表型转变的巨噬细胞的转录组学特征？在项目3中，我们将测试假设， 肺内皮通过Wnt信号转导介导巨噬细胞表型转变，通过修饰线粒体 代谢和启动特定转录程序的表观基因组。在目标1中，我们将定义 内皮Wnt信号在调节肺中单核细胞向巨噬细胞分化中的作用。这里我们将 确定来源于EC的Wnt信号转导调节因子Rspondin 3（Rspo 3）在信号转导以下物质的转变中的作用： 单核细胞到肺巨噬细胞。在目标2中，我们将确定代谢重编程和表观遗传的作用。 修饰巨噬细胞介导表型转变，从而减少肺损伤的程度， 并促进其解决。