Department of Medicine, University of Melbourne, The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia;
J Immunol. 2014 Apr 15;192(8):3540-7. doi: 10.4049/jimmunol.1302864. Epub 2014 Mar 10.
Urokinase plasminogen activator (uPA) and its receptor (uPAR) coordinate a plasmin-mediated proteolytic cascade that has been implicated in cell adhesion, cell motility, and matrix breakdown, for example, during inflammation. As part of their function during inflammatory responses, macrophages move through tissues and encounter both two-dimensional (2D) surfaces and more complex three-dimensional (3D) interstitial matrices. Based on approaches employing uPA gene-deficient macrophages, plasminogen supplementation, and neutralization with specific protease inhibitors, it is reported in this study that uPA activity is a central component of the invasion of macrophages through a 3D Matrigel barrier; it also has a nonredundant role in macrophage-mediated matrix degradation. For murine macrophages, matrix metalloproteinase-9 activity was found to be required for these uPA-mediated effects. Evidence for a unique role for uPA in the inverse relationship between macrophage adhesion and 2D migration was also noted: macrophage adhesion to vitronectin was enhanced by uPA and blocked by plasminogen activator inhibitor-1, the latter approach also able to enhance in turn the 2D migration on this matrix protein. It is therefore proposed that uPA can have a key role in the inflammatory response at several levels as a central regulator of macrophage 3D invasion, matrix remodeling, and adhesion.
尿激酶型纤溶酶原激活物 (uPA) 及其受体 (uPAR) 协调纤溶酶介导的蛋白水解级联反应，该反应参与细胞黏附、细胞迁移和基质分解等过程，例如在炎症过程中。作为其在炎症反应过程中功能的一部分，巨噬细胞在组织中移动，同时遇到二维 (2D) 表面和更复杂的三维 (3D) 间质基质。本研究采用 uPA 基因缺陷型巨噬细胞、纤溶酶原补充以及特异性蛋白酶抑制剂中和等方法，报道 uPA 活性是巨噬细胞穿过 3D Matrigel 屏障侵袭的核心组成部分；它在巨噬细胞介导的基质降解中也具有非冗余作用。对于小鼠巨噬细胞，基质金属蛋白酶-9 活性被发现是这些 uPA 介导作用所必需的。还注意到 uPA 在巨噬细胞黏附和 2D 迁移之间的反比关系中具有独特作用的证据：uPA 增强了巨噬细胞对玻连蛋白的黏附，而纤溶酶原激活物抑制剂-1 则阻断了这种黏附，后者还能反过来增强在这种基质蛋白上的 2D 迁移。因此，uPA 可以作为巨噬细胞 3D 侵袭、基质重塑和黏附的中心调节剂，在几个层面上在炎症反应中发挥关键作用。
