Research Spotlight: Laboratory of Li Zhang Ph.D.

Core Facilities used: Microscopy Core and FACS Core

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

Department of Physiology and Surgery, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
Alzheimer's Disease Research Laboratory, Harvard Medical School, Charlestown, MA, USA
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, 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.