Stromelysin-2 (MMP10) Moderates Inflammation by Controlling Macrophage Activation

Abstract

Several members of the matrix metalloproteinase (MMP) family control a range of immune processes, such as leukocyte influx and chemokine activity. Stromelysin-2 (MMP10) is expressed by macrophages in numerous tissues after injury; however, little is known of its function. Here, we report that MMP10 is expressed by macrophages in human lungs from patients with cystic fibrosis and induced in mouse macrophages in response to Pseudomonas aeruginosa infection both in vivo and by isolated resident alveolar and bone marrow-derived macrophages (BMDM). Our data indicates that macrophage MMP10 serves a beneficial function in response to acute infection. Whereas wildtype mice survived infection with minimal morbidity, 50% of Mmp10−/− mice died and all showed sustained weight loss (morbidity). Although bacterial clearance and neutrophil influx did not differ between genotypes, macrophage numbers were about 3-fold greater in infected Mmp10−/− lungs than in wildtypes. Adoptive transfer of wildtype BMDM normalized infection-induced morbidity in Mmp10−/− recipients to wildtype levels demonstrating that the protective effect of MMP10 was due to its production by macrophages. Both in vivo and in cultured alveolar macrophages and BMDM, expression of several M1 macrophage markers was elevated, while M2 markers were reduced in Mmp10−/− tissue and cells. Global gene expression analysis revealed that infection-mediated transcriptional changes persisted in Mmp10−/− BMDM long after they were down-regulated in wildtype cells. These results indicate that MMP10 serves a beneficial role in response to acute infection by moderating the pro-inflammatory response of resident and infiltrating macrophages.

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

“…[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.…”

“…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. While the exact mechanism(s) underlying this response is unknown (ie, the substrate MMP-10 acts on to control macrophage function), these studies all concluded that Mmp-10 is an important modifier of macrophage activation in injured tissues.…”

“…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.…”

“…BMDMs and alveolar macrophages were isolated and cultured under sterile techniques as described in detail by McMahan et al 23 and Manicone et al 26 Briefly, for BMDMs, marrow from femurs and tibias of wild-type and Mmp10 −/− mice was recovered by brief centrifugation. Red blood cells were removed by adding lysis buffer (eBioscience, San Diego CA, USA).…”

Early Secretory Antigenic Target-6 Drives Matrix Metalloproteinase-10 Gene Expression and Secretion in Tuberculosis

“…Besides ECM breakdown, MMPs may have additional functional roles in the immune response to infections by modulating cytokine processing, defensin activation (5), or leukocyte influx (19). Recently, a novel role for MMP-10 on macrophage polarization was identified in Pseudomonas aeruginosa infection (20). However, MMP-10 has not been systematically investigated in TB.…”