A chemotactic gradient sequestered on endothelial heparan sulfate induces directional intraluminal crawling of neutrophils
A chemotactic gradient sequestered on endothelial heparan sulfate induces directional intraluminal crawling of neutrophils
复制标题
DOI：
10.1182/blood-2010-01-266072
复制
发表时间：
2010-09-16
期刊：
影响因子：
20.3
通讯作者：
Phillipson, Mia
中科院分区：
文献类型：
--
作者：
Massena, Sara;Christoffersson, Gustaf;Phillipson, Mia
在感染期间，隔离在内皮上的趋化因子诱导循环中的白细胞重新聚集到组织中，在组织中它们沿着趋化因子梯度向受累部位趋化。这项体内研究的目的是确定趋化因子梯度是否在血管内形成，并影响中性粒细胞在血管内的爬行和迁移。将含有巨噬细胞炎性蛋白-2(MIP-2)的凝胶(CXCL2)放置在麻醉野生型小鼠或含有截短的硫酸肝素(HS)侧链的高表达乙酰肝素酶转基因小鼠(HPA-TG)的提睾肌上，诱导趋化因子梯度。用活体显微镜观察中性粒细胞与内皮细胞的相互作用，用共聚焦显微镜检测趋化因子梯度。与均一的血管外趋化因子浓度(MIP-2超融合)相比，局部血管外趋化因子释放(MIP-2凝胶)诱导中性粒细胞沿着固定在内皮上的趋化梯度定向爬行，并加速中性粒细胞向靶组织的募集。内皮细胞趋化因子的隔离仅发生在小静脉中，并且是HS依赖的，HPA-TG小鼠的中性粒细胞表现出随机爬行。尽管HPA-TG小鼠和野生型小鼠的中性粒细胞贴壁数量相似，但HPA-TG小鼠爬行的改变转化为中性粒细胞迁出数量的减少，最终降低了清除细菌感染的能力。总而言之，内皮HS隔离的血管内趋化因子梯度有效地将爬行的白细胞导向感染部位附近的移行部位。(血。2010；116(11)：1924-1931)
During infection, chemokines sequestered on endothelium induce recruitment of circulating leukocytes into the tissue where they chemotax along chemokine gradients toward the afflicted site. The aim of this in vivo study was to determine whether a chemokine gradient was formed intravascularly and influenced intraluminal neutrophil crawling and transmigration. A chemokine gradient was induced by placing a macrophage inflammatory protein-2 (MIP-2)-containing (CXCL2) gel on the cremaster muscle of anesthetized wild-type mice or heparanase-overexpressing transgenic mice (hpa-tg) with truncated heparan sulfate (HS) side chains. Neutrophil-endothelial interactions were visualized by intravital microscopy and chemokine gradients detected by confocal microscopy. Localized extravascular chemokine release (MIP-2 gel) induced directed neutrophil crawling along a chemotactic gradient immobilized on the endothelium and accelerated their recruitment into the target tissue compared with homogeneous extravascular chemokine concentration (MIP-2 super-fusion). Endothelial chemokine sequestration occurred exclusively in venules and was HS-dependent, and neutrophils in hpa-tg mice exhibited random crawling. Despite similar numbers of adherent neutrophils in hpa-tg and wild-type mice, the altered crawling in hpa-tg mice was translated into decreased number of emigrated neutrophils and ultimately decreased the ability to clear bacterial infections. In conclusion, an intravascular chemokine gradient sequestered by endothelial HS effectively directs crawling leukocytes toward transmigration loci close to the infection site. (Blood. 2010; 116(11): 1924-1931)