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J Clin Invest. 2008 Sep;118(9):3012-24. doi: 10.1172/JCI32750.

Inflammatory macrophage migration requires MMP-9 activation by plasminogen in mice.

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1
Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Cardiovascular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195, USA.

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.

PMID:
18677407
PMCID:
PMC2491456
DOI:
10.1172/JCI32750
[Indexed for MEDLINE]
Free PMC Article
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