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

Chunzhang Cao, Daniel A. Lawrence, Yang Li, Christine A F Von Arnim, Joachim Herz, Enming J. Su, Alexandra Makarova, Bradley T. Hyman, Dudley K. Strickland, Li Zhang

Research output: Contribution to journalArticle

131 Scopus citations

Abstract

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).

Original languageEnglish (US)
Pages (from-to)1860-1870
Number of pages11
JournalEMBO Journal
Volume25
Issue number9
DOIs
StatePublished - May 3 2006

Keywords

  • Inflammation
  • Integrin Mac-1
  • LRP
  • Macrophage
  • Migration

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Cao, C., Lawrence, D. A., Li, Y., Von Arnim, C. A. F., Herz, J., Su, E. J., Makarova, A., Hyman, B. T., Strickland, D. K., & Zhang, L. (2006). Endocytic receptor LRP together with tPA and PAI-1 coordinates Mac-1-dependent macrophage migration. EMBO Journal, 25(9), 1860-1870. https://doi.org/10.1038/sj.emboj.7601082