1 research outputs found
MMP-12, Secreted by Pro-Inflammatory Macrophages, Targets Endoglin in Human Macrophages and Endothelial Cells
Upon inflammation, monocyte-derived macrophages (MF) 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 e cient initial response
(GM-MF) and a good resolution (M-MF) of the inflammatory process. The functional activity of
polarized MF 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 MF
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 MF secretome involved in
the shedding of soluble endoglin. We find that the GM-MF secretome contains metalloprotease 12
(MMP-12), a GM-MF specific marker that may account for the anti-angiogenic activity of the GM-MF
secretome. Cell surface endoglin is present in both GM-MF and M-MF, but soluble endoglin is
only detected in GM-MF 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 MF and
endothelial cells. These data demonstrate a direct correlation between GM-MF polarization, MMP-12,
and soluble endoglin expression and function. By targeting endothelial cells, MMP-12 may represent
a novel mediator involved in vascular homeostasis.Ministerio de Ciencia, Innovación y Universidades of Spain
(SAF2013-43421-R to C.B.; SAF2017-83785-R and SAF2014-23801 to A.L.C.)Consejo Superior de Investigaciones
Cientificas (201920E022 to C.B.)Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER;
ISCIII-CB06/07/0038 to C.B.)Czech Republic Specific University Research (SVV-260414 to P.N.)CIBERER is
an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain supported by FEDER fundsM.A. was funded
with a fellowship from Ministerio de Ciencia e Innovación (BES-2008-003888)M.V. was supported by a short-term
mobility fellowship from the European Erasmus Programm