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  • The EMBO Journal (2006) 25, 1860 - 1870
  • doi:10.1038/sj.emboj.7601082

Published online: 6 April 2006

Endocytic receptor LRP together with tPA and PAI-1 coordinates Mac-1-dependent macrophage migration

Chunzhang Cao1, Daniel A Lawrence2, Yang Li1, Christine AF 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
  2. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
  3. Alzheimer's Disease Research Laboratory, Harvard Medical School, Charlestown, MA, USA
  4. Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA

Correspondence to:

Li Zhang, Departments of Physiology and Surgery, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, 800 W. Baltimore Street, Baltimore, MD 21201, USA. Tel.: +1 410 706 8040; Fax: +1 410 706 8121; E-mail: LiZhang@som.umaryland.edu

Received 22 April 2005; Accepted 15 March 2006

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).

  • Keywords:

    • inflammation,
    • integrin Mac-1,
    • LRP,
    • macrophage,
    • migration