MMP-12, Secreted by Pro-Inflammatory Macrophages, Targets Endoglin in Human Macrophages and Endothelial Cells
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AuthorAristorena, Mikel; Gallardo-Vara, Eunate; Vicen, Matej; de Las Casas-Engel, Mateo; Ojeda-Fernandez, Luisa; Nieto, Concepción; Blanco, Francisco J.; Valbuena-Diez, Ana C.; Botella, Luisa M.; Nachtigal, Petr; Corbi, Angel L.; Colmenares, María; Bernabeu, Carmelo
Aristorena, M., Gallardo-Vara, E., Vicen, M., de Las Casas-Engel, M., Ojeda-Fernandez, L., Nieto, C., ... & Corbi, A. L. (2019). MMP-12, Secreted by Pro-Inflammatory Macrophages, Targets Endoglin in Human Macrophages and Endothelial Cells. International journal of molecular sciences, 20(12), 3107.
SponsorshipMinisterio 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 funds; M.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 Programme
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.