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- Title
Inflammatory macrophage migration requires MMP-9 activation by plasminogen in mice.
- Authors
Yanqing Gong; Hart, Erika; Shchurin, Aleksey; Hoover-Plow, Jane; Gong, Yanqing
- 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.
- Subjects
MACROPHAGES; PLASMINOGEN; LABORATORY rats; LEUCOCYTES; INFLAMMATION; BLOOD plasma; ABDOMINAL aortic aneurysms; FIBRINOLYTIC agents; ANIMAL experimentation; BIOCHEMISTRY; BIOLOGICAL models; CELL motility; COMBINATION drug therapy; COLLAGEN; COMPARATIVE studies; EXTRACELLULAR space; GLYCOPROTEINS; PHENOMENOLOGY; RESEARCH methodology; MEDICAL cooperation; MEMBRANE proteins; MICE; PROTEOLYTIC enzymes; RESEARCH; EVALUATION research; GENETIC carriers; METABOLISM
- Publication
Journal of Clinical Investigation, 2008, Vol 118, Issue 9, p3012
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI32750