Laboratory of Li Zhang Ph.D.
Endocytic receptor LRP together with tPA and PAI-1 coordinates Mac-1-dependent macrophage migration
Chunzhang Cao1, Daniel A Lawrence2, Yang Li1, Christine A F Von Arnim3, Joachim Herz4, Enming J Su2, Alexandra Makarova3, Bradley T Hyman3, Dudley K Strickland1 and Li Zhang1
1 Department of Physiology and Surgery, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA
|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).|
A model for macrophage migration within an inflammatory environment. Stimulated macrophages attach to the extracellular matrix via the tPA/fibrin binary complex (Step 1) and move forward. Fibrin at the trailing edge is partially degraded by tPA-mediated fibrinolysis. PAI-1-neutralized tPA by which it links the adhesion complex to LRP (Step 2). LRP engagement results in a switch from cell adhesion to cell detachment and integrin internalization (Step 3). The internalized Mac-1/LRP complex is returned to the cell surface (Step 4), moves to the cell leading edge (Step 5), and the cycle starts over again. Thus, PAI-1 and LRP, functioning as a master switch, ensure cell attachment, detachment, and integrin recycling to proceed properly in time and in space, leading to efficient cell migration.