Cao Chunzhang, Lawrence Daniel A, Li Yang, Von Arnim Christine A F, Herz Joachim, Su Enming J, Makarova Alexandra, Hyman Bradley T, Strickland Dudley K, Zhang Li
Department of Physiology and Surgery, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, 21201, USA.
EMBO J. 2006 May 3;25(9):1860-70. doi: 10.1038/sj.emboj.7601082. Epub 2006 Apr 6.
Migration of activated macrophages is essential for resolution of acute inflammation and the initiation of adaptive immunity. Here, we show that efficient macrophage migration in inflammatory environment depends on Mac-1 recognition of a binary complex consisting of fibrin within the provisional matrix and the protease tPA (tissue-type plasminogen activator). Subsequent neutralization of tPA by its inhibitor PAI-1 enhances binding of the integrin-protease-inhibitor complex to the endocytic receptor LRP (lipoprotein receptor-related protein), triggering a switch from cell adhesion to cell detachment. Genetic inactivation of Mac-1, tPA, PAI-1 or LRP but not the protease uPA abrogates macrophage migration. The defective macrophage migration in PAI-1-deficient mice can be restored by wild-type but not by a mutant PAI-1 that does not interact with LRP. In vitro analysis shows that tPA promotes Mac-1-mediated adhesion, whereas PAI-1 and LRP facilitate its transition to cell retraction. Our results emphasize the importance of ordered transitions both temporally and spatially between individual steps of cell migration, and support a model where efficient migration of inflammatory macrophages depends on cooperation of three physiologically prominent systems (integrins, coagulation and fibrinolysis, and endocytosis).
活化巨噬细胞的迁移对于急性炎症的消退和适应性免疫的启动至关重要。在此，我们表明炎症环境中巨噬细胞的有效迁移取决于Mac-1对由临时基质中的纤维蛋白和蛋白酶tPA（组织型纤溶酶原激活剂）组成的二元复合物的识别。随后，其抑制剂PAI-1对tPA的中和增强了整合素-蛋白酶-抑制剂复合物与内吞受体LRP（脂蛋白受体相关蛋白）的结合，触发从细胞黏附到细胞脱离的转变。Mac-1、tPA、PAI-1或LRP的基因失活而非蛋白酶uPA的失活会消除巨噬细胞的迁移。PAI-1缺陷小鼠中巨噬细胞迁移缺陷可通过野生型而非不与LRP相互作用的突变型PAI-1恢复。体外分析表明，tPA促进Mac-1介导的黏附，而PAI-1和LRP促进其向细胞回缩的转变。我们的结果强调了细胞迁移各个步骤在时间和空间上有序转变的重要性，并支持一种模型，即炎症巨噬细胞的有效迁移取决于三个生理上突出的系统（整合素、凝血和纤维蛋白溶解以及内吞作用）的协同作用。
