Wang Shijun, Dangerfield John P, Young Rebecca E, Nourshargh Sussan
Cardiovascular Medicine Unit, The Eric Bywaters Centre for Vascular Inflammation, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 ONN, UK.
J Cell Sci. 2005 May 1;118(Pt 9):2067-76. doi: 10.1242/jcs.02340. Epub 2005 Apr 19.
The heterogeneous nature of the perivascular basement membrane (composed primarily of laminin and collagen type IV) suggests the existence of an elaborate array of adhesive interactions and possibly proteolytic events in leukocyte migration through this barrier. In this context, blockade of alpha6 integrins (laminin receptors), neutrophil elastase (NE) or both inhibited neutrophil migration through interleukin-1beta (IL-1beta)-stimulated mouse cremasteric venules, as observed by intravital microscopy. Furthermore, analysis of tissues by confocal microscopy indicated a synergistic role for alpha6 integrins and NE in mediating neutrophil migration through the perivascular basement membrane. Using a combined in vitro and in vivo experimental approach, the findings of this study also suggest that alpha6 integrins and NE are mobilized from intracellular stores to the cell surface of transmigrating mouse neutrophils, although these events occur via mechanisms dependent on and independent of platelet/endothelial-cell adhesion molecule 1 (PECAM-1, CD31), respectively. Despite different regulatory mechanisms, blockade of alpha6 integrins or NE inhibited migration of murine neutrophils through laminin-coated filters in vitro. Collectively, the findings suggest that, whereas regulation of the expression of alpha6 integrins and NE occur via different adhesive mechanisms, these molecules might act in a cooperative manner in mediating neutrophil migration through venular walls, in particular the perivascular basement membrane.
血管周围基底膜（主要由层粘连蛋白和IV型胶原蛋白组成）的异质性表明，在白细胞穿过该屏障的迁移过程中，存在一系列复杂的黏附相互作用以及可能的蛋白水解事件。在此背景下，通过活体显微镜观察发现，阻断α6整合素（层粘连蛋白受体）、中性粒细胞弹性蛋白酶（NE）或两者均能抑制中性粒细胞通过白细胞介素-1β（IL-1β）刺激的小鼠提睾肌小静脉的迁移。此外，共聚焦显微镜对组织的分析表明，α6整合素和NE在介导中性粒细胞穿过血管周围基底膜的迁移过程中具有协同作用。采用体外和体内相结合的实验方法，本研究的结果还表明，α6整合素和NE从小鼠迁移中性粒细胞的细胞内储存部位转运至细胞表面，尽管这些事件分别通过依赖和不依赖血小板/内皮细胞黏附分子1（PECAM-1，CD31）的机制发生。尽管调控机制不同，但阻断α6整合素或NE均可抑制小鼠中性粒细胞在体外通过层粘连蛋白包被的滤膜的迁移。总的来说，这些发现表明，虽然α6整合素和NE的表达调控通过不同的黏附机制发生，但这些分子可能以协同方式介导中性粒细胞穿过小静脉壁，特别是血管周围基底膜的迁移。
