title: Endocytic receptor LRP together with tPA and PAI-1 coordinates Mac-1-dependent macrophage migration.
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).
authors.affiliation: Department of Physiology and Surgery, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, 21201, USA.
authors.forename: Chunzhang
authors.initials: C
authors.lastname: Cao
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Lawrence
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Christine A F
authors.initials: CA
authors.lastname: Von Arnim
authors.forename: Joachim
authors.initials: J
authors.lastname: Herz
authors.forename: Enming J
authors.initials: EJ
authors.lastname: Su
authors.forename: Alexandra
authors.initials: A
authors.lastname: Makarova
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.forename: Dudley K
authors.initials: DK
authors.lastname: Strickland
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D004705:Endocytosis; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D019426:Integrases / Q000378:metabolism; D026502:LDL-Receptor Related Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D016177:Macrophage-1 Antigen / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism
chemical_list: D026502:LDL-Receptor Related Proteins; D016177:Macrophage-1 Antigen; D017395:Plasminogen Activator Inhibitor 1; D014764:Viral Proteins; D005340:Fibrinogen; C045073:Cre recombinase; D019426:Integrases; D010959:Tissue Plasminogen Activator