Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo.
Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo.
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从血液到无菌或感染性组织损伤的血管外部位的神经元募集是早期先天性免疫应答的标志，并且导致细胞从血流中退出的分子事件已经被很好地定义。一旦在血管外，单个中性粒细胞往往表现出极其协调的趋化性和集群形成，让人想起昆虫的群集行为。在炎症组织的复杂性中，在单细胞和群体水平上指导这种反应的分子参与者是未知的。在无菌损伤和感染的小鼠模型中使用双光子活体显微镜，我们显示了由脂质白三烯B4介导的中性粒细胞之间的细胞间信号中继的关键作用，其急剧放大局部细胞死亡信号以增强高度定向的间质中性粒细胞募集的半径。整联蛋白受体被认为是长距离迁移的载体，但当聚集的中性粒细胞重新排列真皮的胶原纤维网络以在伤口中心形成无胶原区时，整联蛋白受体在维持密集的细胞簇中具有先前未被认识到的作用。在这种新形成的环境中，整合素与嗜中性粒细胞衍生的白三烯B4和其他化学引诱物一起促进局部嗜中性粒细胞相互作用，同时形成紧密的伤口密封。该伤口密封具有停止生长的边界，其与单核细胞和巨噬细胞在移位的胶原纤维边缘的晚期募集动力学一致。总之，这些数据提供了一个初始的分子图谱的因素，有助于中性粒细胞群集在血管外空间的受损组织。它们揭示了局部事件是如何在大范围内传播的，以及自动信号是如何产生协调的、自组织的嗜热菌群行为的，这种行为将伤口或感染部位与周围的活组织隔离开来。
Neutrophil recruitment from blood to extravascular sites of sterile or infectious tissue damage is a hallmark of early innate immune responses, and the molecular events leading to cell exit from the bloodstream have been well defined. Once outside the vessel, individual neutrophils often show extremely coordinated chemotaxis and cluster formation reminiscent of the swarming behaviour of insects. The molecular players that direct this response at the single-cell and population levels within the complexity of an inflamed tissue are unknown. Using two-photon intravital microscopy in mouse models of sterile injury and infection, we show a critical role for intercellular signal relay among neutrophils mediated by the lipid leukotriene B4, which acutely amplifies local cell death signals to enhance the radius of highly directed interstitial neutrophil recruitment. Integrin receptors are dispensable for long-distance migration, but have a previously unappreciated role in maintaining dense cellular clusters when congregating neutrophils rearrange the collagenous fibre network of the dermis to form a collagen-free zone at the wound centre. In this newly formed environment, integrins, in concert with neutrophil-derived leukotriene B4 and other chemoattractants, promote local neutrophil interaction while forming a tight wound seal. This wound seal has borders that cease to grow in kinetic concert with late recruitment of monocytes and macrophages at the edge of the displaced collagen fibres. Together, these data provide an initial molecular map of the factors that contribute to neutrophil swarming in the extravascular space of a damaged tissue. They reveal how local events are propagated over large-range distances, and how auto-signalling produces coordinated, self-organized neutrophil-swarming behaviour that isolates the wound or infectious site from surrounding viable tissue.