title: Urokinase plasminogen activator is a central regulator of macrophage three-dimensional invasion, matrix degradation, and adhesion.
abstract: Urokinase plasminogen activator (uPA) and its receptor (uPAR) coordinate a plasmin-mediated proteolytic cascade that has been implicated in cell adhesion, cell motility, and matrix breakdown, for example, during inflammation. As part of their function during inflammatory responses, macrophages move through tissues and encounter both two-dimensional (2D) surfaces and more complex three-dimensional (3D) interstitial matrices. Based on approaches employing uPA gene-deficient macrophages, plasminogen supplementation, and neutralization with specific protease inhibitors, it is reported in this study that uPA activity is a central component of the invasion of macrophages through a 3D Matrigel barrier; it also has a nonredundant role in macrophage-mediated matrix degradation. For murine macrophages, matrix metalloproteinase-9 activity was found to be required for these uPA-mediated effects. Evidence for a unique role for uPA in the inverse relationship between macrophage adhesion and 2D migration was also noted: macrophage adhesion to vitronectin was enhanced by uPA and blocked by plasminogen activator inhibitor-1, the latter approach also able to enhance in turn the 2D migration on this matrix protein. It is therefore proposed that uPA can have a key role in the inflammatory response at several levels as a central regulator of macrophage 3D invasion, matrix remodeling, and adhesion.
authors.affiliation: Department of Medicine, University of Melbourne, The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia;
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Fleetwood
authors.forename: Adrian
authors.initials: A
authors.lastname: Achuthan
authors.forename: Heidi
authors.initials: H
authors.lastname: Schultz
authors.forename: Anneline
authors.initials: A
authors.lastname: Nansen
authors.forename: Kasper
authors.initials: K
authors.lastname: Almholt
authors.forename: Pernille
authors.initials: P
authors.lastname: Usher
authors.forename: John A
authors.initials: JA
authors.lastname: Hamilton
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D059748:Proteolysis; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
chemical_list: D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9