MMP-10 Regulates Collagenolytic Activity of Alternatively Activated Resident Macrophages

Abstract

MMP-10 is expressed by macrophages and epithelium in response to injury, but its functions in wound repair are unknown. We observed increased collagen deposition and skin stiffness in Mmp10−/− wounds with no difference in collagen expression or re-epithelialization. Increased collagen deposition in Mmp10−/− wounds was accompanied by less collagenolytic activity and reduced expression of specific metallocollagenases, particularly MMP-8 and MMP-13, where MMP-13 was the key collagenase. Ablation and adoptive transfer approaches and cell-based models demonstrated that the MMP-10-dependent collagenolytic activity was a product of alternatively activated (M2) resident macrophages. These data demonstrate a critical role for macrophage MMP-10 in controlling the tissue remodeling activity of macrophages and moderating scar formation during wound repair.

Stromelysin-2 (MMP-10) facilitates clearance and moderates inflammation and cell death following lung exposure to long multiwalled carbon nanotubes

“…8 In addition, our group and others have shown that Mmp10 is a critical determinant of macrophage responses and differentiation status in models of acute colon injury, 22 skin wounds, 18 and lung infection with Pseudomonas aeruginosa. 23 Notably, in both the skin wound and lung infection models, adoptive transfer of wild-type macrophages into Mmp10 −/− mice was sufficient to rescue the principal phenotypes (excess scar in skin wounds; morbidity in lung infection) observed in Mmp10 −/− animals.…”

“…With respect to mechanism, we propose that MMP10 sheds a protein on the surface of macrophages and that this proteolytic processing mediates outside-in signaling that affects the activation state of these cells and expression of inflammatory mediators. Because we observed overlapping responses in macrophages both in vivo and in cell culture, 18,23 it is likely that MMP10 controls macrophage activation via a cell autonomous mechanism. Although we do not yet know the critical substrate, identifying this macrophage protein is a major goal of our group.…”

“…16,17 Like several MMPs, MMP-10 is not expressed in unchallenged tissues, but in response to a variety of insults, including injury and infection, it is induced by macrophages and epithelial cells in many organs, including the lung. [18][19][20][21] Studies with Mmp10 −/− mice indicate that MMP-10 functions to control the activation status of macrophages. 18,22,23 In this study, we report a protective role for macrophage MMP-10 in the acute pulmonary response to MWCNTs.…”

“…[18][19][20][21] Studies with Mmp10 −/− mice indicate that MMP-10 functions to control the activation status of macrophages. 18,22,23 In this study, we report a protective role for macrophage MMP-10 in the acute pulmonary response to MWCNTs. We found that following aspiration of long MWCNTs into the lung, expression of MMP-10 was induced, and promoted clearance of these nanoparticles from the lung, and mononuclear cell survival, and moderated inflammation and airway fibrosis.…”

Matrix Metalloproteinase 10 Degradomics in Keratinocytes and Epidermal Tissue Identifies Bioactive Substrates With Pleiotropic Functions*

“…MMP10 released from hepatocytes and macrophages positively contributed to liver regeneration (10), whereby it promoted hepatocarcinogenesis in a complicated crosstalk with chemokine signaling (11). Most recently, Rohani et al dem-onstrated a role for macrophage-derived MMP10 in moderating scar formation by controlling collagenase activity of dermal macrophages (12).…”