title: Inflammatory macrophage migration requires MMP-9 activation by plasminogen in mice.
abstract: Inflammation plays a critical role in the development of cardiovascular diseases. Infiltration of leukocytes to sites of injury requires their exit from the blood and migration across basement membrane; this process has been postulated to require remodeling of the ECM. Plasminogen (Plg) is a protease that binds to the ECM and, upon conversion to plasmin, degrades multiple ECM proteins. In addition, plasmin directly activates MMPs. Here, we used Plg(-/-) mice to investigate the role of Plg in inflammatory leukocyte migration. After induction of peritonitis by thioglycollate injection, we found that Plg(-/-) mice displayed diminished macrophage trans-ECM migration and decreased MMP-9 activation. Furthermore, injection of the active form of MMP-9 in Plg(-/-) mice rescued macrophage migration in this model. We used periaortic application of CaCl2 to induce abdominal aortic aneurysm (AAA) and found that Plg(-/-) mice displayed reduced macrophage infiltration and were protected from aneurysm formation. Administration of active MMP-9 to Plg(-/-) mice promoted macrophage infiltration and the development of AAA. These data suggest that Plg regulates macrophage migration in inflammation via activation of MMP-9, which, in turn, regulates the ability of the cells to migrate across ECM. Thus, targeting the Plg/MMP-9 pathway may be an attractive approach to regulate inflammatory responses and AAA development.
authors.affiliation: Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Cardiovascular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195, USA.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Gong
authors.forename: Erika
authors.initials: E
authors.lastname: Hart
authors.forename: Aleksey
authors.initials: A
authors.lastname: Shchurin
authors.forename: Jane
authors.initials: J
authors.lastname: Hoover-Plow
mesh_terms: D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000235:genetics; D002465:Cell Movement; D003094:Collagen / Q000737:chemistry / Q000378:metabolism; D004338:Drug Combinations; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism*; D006579:Heterozygote; D007249:Inflammation; D007797:Laminin / Q000737:chemistry; D008264:Macrophages / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010958:Plasminogen / Q000378:metabolism*; D011509:Proteoglycans / Q000737:chemistry
chemical_list: D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D010958:Plasminogen; D003094:Collagen; D020780:Matrix Metalloproteinase 9