Vascular endothelial cells and macrophages coordinate neutrophil trafficking in inflammation

血管内皮细胞和巨噬细胞在炎症中协调中性粒细胞的运输 摘要 许多病理情况的发生是由于或涉及免疫细胞运输和/或效应器功能的失调。 特别是，被称为中性粒细胞(PMN)的天然免疫细胞的组织积累对宿主来说是必不可少的 防御和组织动态平衡，往往会导致炎症加剧。 跨过内皮屏障是组织PMN效应功能的第一个关键调控步骤。许多 然而，涉及这种级联反应的受体-配体相互作用已经被很好地定义，然而，启动和 终止这一进程则知之甚少。我们的数据确定了内皮细胞的一种新的协同功能 (2)血管内皮细胞(ECs)和间质巨噬细胞(Mϕ，S)参与调节炎症黏膜的这一重要过程。我们发现 EC特有的线索将MϕS吸引到血管壁，MϕS延伸细胞突起形成瞬变 与ECs的交界处。通过这些结合作用和细胞外小泡(EV)的释放， 转运调节的microRNA，MϕS可以将ECs中必要的信号事件转导到优先 适应PMN瞬变电磁波。因此，该提案的总体目标是定义机制和信令事件 调节间质Mϕ的募集和与血管壁的接触，以局部启动EC反应和引导 炎症粘膜中性粒细胞的超微结构。我们将使用最先进的双光子活体显微镜(2pIVM)，相关 记者与KO小鼠建立粘膜炎症模型1.确定S如何招募间质Mϕ 与炎症组织中的血管内皮细胞相互作用。2.明确MϕS启动血管内皮细胞形成的机制 PMN的透射电子显微镜热点。3.确定需要在多大程度上启动血管内皮细胞的Mϕ(热点形成) 用于PMN的透射电子显微镜和组织炎症的消退。我们的研究将定义PMN贩运的新机制， 并可能寻找新的分子靶点来提高炎症的消退。

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.