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

Gong Y. et al. 2008. J.Clin. Invest. 118, 3012-3024

Speaker: Jo-Shi Lin (林若曦)                  Time: 14:00~15:00, Oct. 1, 2008

Commentator: Dr. Ai-Li Shiau (蕭璦莉老師)     Place: Room 601

Abstract:

Abdominal aortic aneurysms (AAAs) represent a degenerative process of the abdominal aorta that is often attributed to atherosclerosis. In recently studies, there are evidences indicated that AAA is also associated with chronic inflammation¹.  The chronic inflammation was characterized asextensive infiltration of inflammatory cells, such as macrophage and lymphocytes. These cells are thought to elicit an inflammatory cytokine cascade, culminating in the degeneration of aortic connective tissue. Cell transmigration was involved in macrophage infiltration; this process required remodeling of the ECM. ECM remodeling requires a panel of protease, including the plasminogen (Plg) and matrix metalloproteinases (MMPs). Plg, the zymosan for plasmin, has been reported to involve in inflammatory cell recruitment. Plasmin can also activate other ECM-degrading proteinases, such as MMP-3, MMP-9, MMP-12, and MMP-13². However, the Plg-mediated ECM turnover involved in AAA is still unclear. To find out the mechanism underlying Plg-regulated ECM turnover in vivo, the authors designed 2 experimental animal models: a peritoneal inflammatory response induced by thioglycollate and an AAA model induced by CaCl₂. In the thioglycollate-induced peritoneal inflammation experiment, the Plg was required for the macrophage recruitment but not neutrophils. In the Plg^-/- mice, macrophage accumulated in the peritoneal tissue due to the type IV collagen in the peritoneal tissue. The accumulation was due to the activation of MMP-9 indicated the macrophage migration required Plg-mediated active MMP-9. In the CaCl₂-induced AAA model, Plg is required for the pathological progression, including elastin degradation and macrophage recruitment. In conclusion, the authors provides in vivo evidence that Plg/plasmin is required for macrophage recruitment and this role is mediated through activation of MMP-9.

References:

1.      Anidjar, S. et al. 1992. Correlation of inflammatory infiltrate with the enlargement of experimental aortic aneurysms. J. Vasc. Surg. 16:139-147

2.      Lijnen, H.R., et al. 2001. Plasmin and matrix metalloproteinases in vascular remodeling. Thromb. Haemost. 86:324-333