MMP-12, Secreted by Pro-Inflammatory Macrophages, Targets Endoglin in Human Macrophages and Endothelial Cells

Upon inflammation, monocyte-derived macrophages (M Phi) infiltrate blood vessels to regulate several processes involved in vascular pathophysiology. However, little is known about the mediators involved. Macrophage polarization is crucial for a fast and efficient initial response (GM-M Phi) and a good resolution (M-M Phi) of the inflammatory process. The functional activity of polarized M Phi is exerted mainly through their secretome, which can target other cell types, including endothelial cells. Endoglin (CD105) is a cell surface receptor expressed by endothelial cells and M Phi that is markedly upregulated in inflammation and critically involved in angiogenesis. In addition, a soluble form of endoglin with anti-angiogenic activity has been described in inflammation-associated pathologies. The aim of this work was to identify components of the M Phi secretome involved in the shedding of soluble endoglin. We find that the GM-M Phi secretome contains metalloprotease 12 (MMP-12), a GM-M Phi specific marker that may account for the anti-angiogenic activity of the GM-M Phi secretome. Cell surface endoglin is present in both GM-M Phi and M-M Phi, but soluble endoglin is only detected in GM-M Phi culture supernatants. Moreover, MMP-12 is responsible for the shedding of soluble endoglin in vitro and in vivo by targeting membrane-bound endoglin in both M Phi and endothelial cells. These data demonstrate a direct correlation between GM-M Phi polarization, MMP-12, and soluble endoglin expression and function. By targeting endothelial cells, MMP-12 may represent a novel mediator involved in vascular homeostasis.