Inflammatory macrophage migration requires MMP-9 activation by plasminogen in mice
Yanqing Gong1, Erika Hart, Aleksey Shchurin
1Joseph 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.
Insights
Plasminogen (Plg) deficiency reduces inflammatory cell migration and abdominal aortic aneurysm development by inhibiting matrix metalloproteinase-9 (MMP-9) activation. Restoring MMP-9 activity rescues these effects, highlighting the Plg/MMP-9 pathway
Area of Science:
- Cardiovascular Biology
- Inflammation Research
- Protease Biochemistry
Background:
- Inflammation drives cardiovascular diseases, involving leukocyte migration across the extracellular matrix (ECM).
- Plasminogen (Plg) is an ECM-associated protease that, upon activation to plasmin, degrades ECM proteins and activates matrix metalloproteinases (MMPs).
Purpose of the Study:
- To investigate the role of Plasminogen (Plg) in inflammatory leukocyte migration and abdominal aortic aneurysm (AAA) development.
- To elucidate the mechanism involving Plg-mediated activation of matrix metalloproteinase-9 (MMP-9).
Main Methods:
- Utilized Plasminogen-deficient (Plg(-/-)) mice.
- Induced peritonitis using thioglycollate injection to assess leukocyte migration.
- Induced abdominal aortic aneurysm (AAA) via periaortic CaCl2 application.
- Administered active MMP-9 to Plg(-/-) mice to evaluate rescue effects.
Main Results:
- Plg(-/-) mice exhibited significantly reduced macrophage trans-ECM migration and diminished MMP-9 activation following peritonitis induction.
- Plg(-/-) mice were protected from AAA formation, showing reduced macrophage infiltration.
- Administration of active MMP-9 rescued macrophage migration in Plg(-/-) mice and promoted AAA development.
Conclusions:
- Plasminogen (Plg) regulates inflammatory macrophage migration and abdominal aortic aneurysm (AAA) development through the activation of matrix metalloproteinase-9 (MMP-9).
- Targeting the Plg/MMP-9 pathway represents a potential therapeutic strategy for managing inflammatory responses and AAA progression.
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