Vascular endothelial cells and macrophages coordinate neutrophil trafficking in inflammation

标题：炎症中血管内皮细胞和巨噬细胞协调中性粒细胞运输 摘要 许多病理状况的发生是由于或涉及失调的免疫细胞运输和/或效应子功能。 特别是，称为中性粒细胞（PMN）的先天性免疫细胞的组织积累，而对宿主细胞的生长至关重要。 防御和组织稳态，往往导致炎症加剧。 通过内皮屏障是组织PMN效应器功能的第一个关键调节步骤。许多 涉及该级联反应的受体-配体相互作用已经被很好地定义，然而，启动和 终止这一进程不太为人所知。我们的数据确定了一种新的协同功能的内皮细胞 (ECs)和间质巨噬细胞（M β s）在炎症粘膜中调节这一重要过程。我们发现 EC特异性信号将M细胞吸引到血管壁，M细胞延伸细胞突起，形成短暂的 与EC的连接。通过这些结合相互作用和细胞外囊泡（EV）的释放， 转运调节microRNA，M β s可以使EC中必要的信号事件优先 容纳PMN TEM。因此，本提案的总体目标是定义机制和信号事件 其调节间质性M β募集并与血管壁接触以局部引发EC反应并引导 炎性粘膜中的PMN TEM。我们将利用最先进的双光子活体显微镜（2 pIVM）， 报告基因和KO小鼠在粘膜炎症模型中对1.确定间质性M细胞是如何被招募的， 与发炎组织中的血管内皮细胞相互作用。2.定义M β启动血管EC形成的机制 PMN TEM热点。3.确定血管EC（热点形成）所需的M β-预充程度 用于PMN TEM和组织炎症的消退。我们的研究将确定PMN贩运的新机制， 并可能发现新的分子靶点以改善炎症的消退。

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.