Endocytic receptor LRP together with tPA and PAI-1 coordinates Mac-1-dependent macrophage migration.
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).
Cao
Chunzhang
C
Department of Physiology and Surgery, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, 21201, USA.
Lawrence
Daniel A
DA
Li
Yang
Y
Von Arnim
Christine A F
CA
Herz
Joachim
J
Su
Enming J
EJ
Makarova
Alexandra
A
Hyman
Bradley T
BT
Strickland
Dudley K
DK
Zhang
Li
L
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
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