Vascular endothelial cells and macrophages coordinate neutrophil trafficking in inflammation

血管内皮细胞和巨噬细胞协调炎症中的中性粒细胞运输

基本信息

批准号：
10298564
负责人：
Ronen Sumagin
金额：
$ 38.73万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-04 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10298564
关键词：
Actins Acute Adhesions Adhesives Binding Blood Vessels CD31 Antigens Cell Adhesion Molecules Cell physiology Cells Cues Cytoskeletal Modeling Cytoskeleton Data Effector Cell Endothelial Cells Endothelium Event Goals Homeostasis Host Defense Hot Spot Immune Immune response Inflammation Inflammatory Bowel Diseases Injury Intercellular Junctions Knockout Mice Lead Ligands Ligation Mediating MicroRNAs Modeling Molecular Molecular Target Mucositis Mucous Membrane Mus Neutrophil Infiltration Pathologic Physiological Process Regulation Reporter Resolution Signal Transduction Site Tissues Vascular Endothelial Cell Work cadherin 5 cytokine extracellular vesicles healing improved interest interstitial intravital microscopy macrophage migration molecular imaging neutrophil novel novel therapeutic intervention receptor recruit response tissue injury trafficking two-photon vesicular release

项目摘要

Title: Vascular endothelial cells and macrophages coordinate neutrophil trafficking in inflammation Abstract Many pathological conditions occur due to or involve deregulated immune cell trafficking and/or effector function. In particular, tissue accumulation of innate immune cells termed neutrophils (PMN) while essential for host defense and tissue homeostasis, often leads to exacerbated inflammation. Crossing of the endothelial barrier is the first critical regulatory step in tissue PMN effector function. Many receptor-ligand interactions involved this cascade have been well-defined, however, cues that initiate and terminate this process are less understood. Our data identified a novel synergistic function of endothelial cells (ECs) and interstitial macrophages (Mϕs) in regulating this importnant process in inflamed mucosa. We found that EC-specific cues attract Mϕs to the vessel wall, and that Mϕs extend cellular protrusions to form transient junctions with ECs. Through these binding interactions and the release of extracellular vesicles (EVs), which transport regulatory microRNAs, Mϕs can transduce the necessary signaling events in ECs to preferentially accommodate PMN TEM. Thus, the overall goal of this proposal is to define mechanisms and signaling events that regulate interstitial Mϕ recruitment and contact with the vessel wall to locally prime EC responses and guide PMN TEM in inflamed mucosa. We will utilize state-of-the-art 2-photon intravital microscopy (2pIVM), relevant reporter and KO mice in models of mucosal inflammation to 1. Determine how interstitial Mϕs are recruited to interact with vascular ECs in inflamed tissue. 2. Define mechanisms by which Mϕs prime vascular ECs to form PMN TEM hot spots. 3. Determine the extent to which Mϕ-priming of vascular ECs (hot spot formation) is required for PMN TEM and resolution of tissue inflammation. Our studies will define new mechanisms of PMN trafficking, and likely identify new molecular targets to improve resolution of inflammation.

标题：血管内皮细胞和巨噬细胞协调炎症中的中性粒细胞运输抽象的许多病理状况的发生是由于或涉及免疫细胞运输和/或效应器功能失调。特别是，被称为中性粒细胞（PMN）的先天免疫细胞的组织积累对于宿主至关重要防御和组织稳态，通常会导致炎症加剧。穿过内皮屏障是组织中性粒细胞效应功能的第一个关键调节步骤。涉及该级联的受体-配体相互作用已被明确定义，但是，启动和启动的线索我们的数据确定了内皮细胞的一种新的协同功能，但人们对此了解较少。我们发现，细胞（EC）和间质巨噬细胞（Mφs）在调节发炎粘膜的这一重要过程中。 EC 特异性线索将 Mφs 吸引到血管壁，并且 Mφs 延伸细胞突起以形成短暂的通过这些结合相互作用和细胞外囊泡（EV）的释放，运输调节性 microRNA，Mphis 可以优先将 EC 中必要的信号事件转导为因此，该提案的总体目标是定义机制和信令事件。调节间质 Mphi 募集和与血管壁的接触，以局部启动 EC 反应并指导我们将利用最先进的 2 光子活体显微镜 (2pIVM) 来观察发炎的粘膜。粘膜炎症模型中的报告者和 KO 小鼠 1. 确定间质 Mphis 如何被招募到与发炎组织中的血管 EC 相互作用 2. 定义 Mψs 促进血管 EC 形成的机制。 PMN TEM 热点 3. 确定血管 EC 的 Mφ 启动（热点形成）所需的程度。对于中性粒细胞 TEM 和组织炎症的解决，我们的研究将定义中性粒细胞运输的新机制，并可能确定新的分子靶点来改善炎症的解决。