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

• 批准号: 10418796
• 负责人: Ronen Sumagin
• 金额: $ 38.8万
• 依托单位: NORTHWESTERN UNIVERSITY 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: 2021-06-04 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10418796
• 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

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在炎症中协调中性粒细胞运输 抽象的 许多病理状况是由于或涉及放松管制的免疫损耗和/或效应子功能。 特别是，含有嗜中性粒细胞（PMN）的先天免疫小球的组织积累，而对宿主必不可少 防御和组织体内稳态，通常会导致炎症加剧。 内皮屏障的穿越是组织PMN效应函数中的第一个关键调节步骤。许多 但是，涉及该级联的受体 - 配体相互作用已明确定义，但是，启动和 终止此过程的理解较少。我们的数据确定了内皮细胞的新型协同功能 （ECS）和间质巨噬细胞（Mϕ）在确定发炎的粘膜中这一重要过程时。我们发现 该EC特异性提示吸引了M ϕs到容器壁上，并且M ϕ扩展了细胞蛋白以形成瞬态 与ECS的交界处。通过这些结合相互作用和细胞外蔬菜（EV）的释放， 传输调节性microRNA，M ϕ可以将EC中的必要信号事件传输到优先 可容纳PMN TEM。这是该提案的总体目标是定义机制和信号事件 调节间质的M ϕ募集并与容器壁接触以局部质量EC反应和指导 PMN TEM在发炎的粘膜中。我们将利用最先进的2光子插入式显微镜（2PIVM），相关 粘膜注射模型中的记者和KO小鼠至1。确定如何募集间质Mϕ 与发炎组织中的血管EC相互作用。 2。定义M ϕs素血管EC形成的机制 PMN TEM热点。 3。确定需要多大的血管EC酸化（热点形成） 用于PMN TEM和组织注射的分辨率。我们的研究将定义PMN贩运的新机制， 并可能确定新的分子靶标，以改善炎症的分辨率。