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

Abstract

Upon inflammation, monocyte-derived macrophages (MΦ) 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-MΦ) and a good resolution (M-MΦ) of the inflammatory process. The functional activity of polarized MΦ 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 MΦ 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 MΦ secretome involved in the shedding of soluble endoglin. We find that the GM-MΦ secretome contains metalloprotease 12 (MMP-12), a GM-MΦ specific marker that may account for the anti-angiogenic activity of the GM-MΦ secretome. Cell surface endoglin is present in both GM-MΦ and M-MΦ, but soluble endoglin is only detected in GM-MΦ 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 MΦ and endothelial cells. These data demonstrate a direct correlation between GM-MΦ polarization, MMP-12, and soluble endoglin expression and function. By targeting endothelial cells, MMP-12 may represent a novel mediator involved in vascular homeostasis.

Endoglin: Beyond the Endothelium

“…Cell-surface endoglin expression is also regulated via receptor shedding. Our previous work showed that the membrane-bound protease Matrix Metalloproteinase-14 (MMP-14, also known as Membrane Type-1 MMP) is able to cleave endoglin in the extracellular domain close to the cell membrane [25], and the same phenomenon was seen by Aristorena et al for MMP-12 secreted by inflammatory macrophages [26], which generated a soluble form of endoglin (sol-eng). Sol-eng can disturb vascular remodeling and maintenance, resulting in vascular abnormalities.…”

Directionality of Macrophages Movement in Tumour Invasion: A Multiscale Moving-Boundary Approach

“…So now we consider not only the contribution of cancer cells but also that of the macrophages to the secretion of the various classes of matrix metalloproteinases (Aristorena et al. 2019 ; Huang et al. 2012 ).…”

Inflammation shapes pathogenesis of murine arrhythmogenic cardiomyopathy

“…More detailed statistic data are provided in Supplementary Table 5 ◂ the F4/80 staining was again fainter. We then studied the mRNA expression of osteopontin (Spp1), which is a marker for reparative macrophages [49,55,57], the matrix metalloproteinase 12, a macrophage-specific elastase expressed in pro-inflammatory macrophages [4], and the lectin YM1 (CHI3L3), which is an indicator for reparative or alternatively activated macrophages [45]. Spp1 mRNA stayed elevated and continued to be significantly increased in 8 and 12 week-old Dsg2 MT mice (Fig.…”