Extravascular dynamics and positioning of innate leukocytes and their functional impact for the immune system

先天免疫细胞在炎症和感染部位代表宿主免疫防御的前线。一些白细胞（中性粒细胞、单核细胞）在血液中循环，只在急性炎症部位离开血管，而其他天然细胞（巨噬细胞、树突状细胞、肥大细胞）已经存在于外周组织或淋巴器官中。虽然白细胞外渗的编排已被广泛研究，并在不同的机械步骤中得到完善，但对协调血管外先天白细胞行为的级联事件知之甚少。体外研究已经确定了大量的先天免疫细胞的激活细胞因子和趋化指导信号，但我们几乎不知道这些因素的来源以及它们如何共同作用以协调血管外空间的细胞动力学。我们知道，每一种先天白细胞亚型在分子上都是不同的，并进化出特殊的效应功能。然而，我们才刚刚开始了解基本的体内机制，使它们能够特定的血管外组织定位，指导它们的迁移路径并促进它们之间的细胞相互作用。对这些血管外事件的进一步了解将解释先天白细胞如何在组织损伤、病原体进入或过敏原暴露期间建立有效的免疫反应，从而恢复和确保生物体的健康。目前的拨款提案解决了对动态免疫反应的理解具有广泛重要性的问题，并将致力于研究先天免疫细胞如何(1)感知、检测和消除组织中的损伤，(2)在损伤、炎症和过敏反应期间相互沟通以优化先天免疫反应的协调，以及(3)启动适应性免疫反应的战略定位。这些研究旨在确定分子作为血管外白细胞动力学治疗干预的潜在靶点，并为靶向治疗调节免疫反应和改善炎症、感染性或过敏性疾病奠定基础。

Innate immune cells represent the front line of host immune defense at sites of inflammation and infection. Some leukocytes (neutrophils, monocytes) circulate through the bloodstream and only exit the vessel at sites of acute inflammation, whereas other innate cells (macrophages, dendritic cells, mast cells) already reside in peripheral tissues or lymphoid organs. While the choreography of leukocyte extravasation has been extensively studied and refined in mechanistically distinct steps, much less is known about the cascade of events that coordinates innate leukocyte behavior outside the vessel. In vitro studies have identified a huge number of activating cytokines and chemotactic guiding signals for innate immune cells, but we hardly understand where these factors originate from and how they act together to coordinate cellular dynamics in the extravascular space. We know that each innate leukocyte subtype is molecularly distinct and evolved special effector functions. However, we are only starting to understand the basic in vivo mechanisms that enable their specific extravascular tissue positioning, guide their migration paths and foster cellular interactions between them. Further insights into these extravascular events will explain how innate leukocytes mount an efficient immune response during tissue injury, pathogen entry or allergen exposure, and thus restore and ensure health to the organism.The present grant proposal addresses questions of broad importance for the understanding of the dynamic immune response and will aim to investigate how innate immune cells (1) sense, detect and eliminate damage in the tissue, (2) communicate with each other for optimal coordination of the innate immune repsonse during wounding, inflammation and anaphylaxis and (3) strategically position to initiate adaptive immune responses. These studies aim at identifying molecules as potential targets for therapeutic intervention with extravascular leukocyte dynamics and laying the groundwork for targeted therapies to modulate immune responses and ameliorate inflammatory, infectious or anaphylactic conditions.