Macrophages and Development of Immunity Unit, Department of Developmental and Stem Cell Biology, Institut Pasteur, Paris, France.
Curr Biol. 2012 Dec 18;22(24):2375-82. doi: 10.1016/j.cub.2012.11.018. Epub 2012 Dec 6.
Chemokines are essential in many cell migration processes, including the recruitment of leukocytes to sites of infection. In the latter context, chemokines promote leukocyte extravasation into the relevant tissue through a well-studied cascade of events. It is widely believed that chemokines further guide leukocytes within tissues via chemotaxis, the directed migration along gradients of soluble ligands. However, the basic mechanism of chemokine action within tissues has yet to be formally addressed in vivo. We identified a chemokine (zCxcl8) that recruits zebrafish neutrophils to infection loci and analyzed its function directly within interstitial tissues of living larvae. Using noninvasive imaging and a controlled cellular source of zCxcl8, we found that zCxcl8 guides neutrophils in a 2-fold manner: by biasing cell speed according to direction (orthotaxis) and by restricting cell motility near the source. We further show that zCxcl8 establishes tissue-bound gradients in vivo by binding to heparan sulfate proteoglycans (HSPGs). Inhibition of this interaction compromised both directional guidance and restriction of neutrophil motility. Thus, by interacting with extracellular HSPGs, chemokines establish robust surface-bound (haptotactic) gradients that mediate both recruitment and retention of leukocytes at sites of infection.
趋化因子在许多细胞迁移过程中是必不可少的，包括白细胞向感染部位的募集。在后一种情况下，趋化因子通过一系列研究充分的事件促进白细胞渗出到相关组织。人们普遍认为，趋化因子通过趋化作用（沿着可溶性配体梯度的定向迁移）在组织内进一步引导白细胞。然而，趋化因子在组织内的作用的基本机制尚未在体内得到正式解决。我们鉴定了一种趋化因子（zCxcl8），它将斑马鱼中性粒细胞募集到感染部位，并在活体幼虫的间质组织中直接分析其功能。使用非侵入性成像和 zCxcl8 的受控细胞来源，我们发现 zCxcl8 以两种方式引导中性粒细胞：根据方向（正趋化性）使细胞速度偏向和在源附近限制细胞迁移。我们进一步表明，zCxcl8 通过与硫酸乙酰肝素蛋白聚糖 (HSPG) 结合在体内建立组织边界梯度。抑制这种相互作用会损害中性粒细胞运动的定向引导和限制。因此，通过与细胞外 HSPG 相互作用，趋化因子建立了强大的表面结合（趋化性）梯度，介导白细胞在感染部位的募集和保留。
