Premium
Endocytic receptor LRP together with tPA and PAI‐1 coordinates Mac‐1‐dependent macrophage migration
Author(s) -
Cao Chunzhang,
Lawrence Daniel A,
Li Yang,
Von Arnim Christine AF,
Herz Joachim,
Su Enming J,
Makarova Alexandra,
Hyman Bradley T,
Strickland Dudley K,
Zhang Li
Publication year - 2006
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601082
Subject(s) - biology , microbiology and biotechnology , integrin , endocytic cycle , cell migration , endocytosis , macrophage , receptor , plasminogen activator , cell adhesion , cell , biochemistry , in vitro , endocrinology
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).