Stromelysin-2 (MMP10) Moderates Inflammation by Controlling Macrophage Activation.
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. In this study, 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 wild-type 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 ∼3-fold greater in infected Mmp10(-/-) lungs than in wild-types. Adoptive transfer of wild-type BMDM normalized infection-induced morbidity in Mmp10(-/-) recipients to wild-type 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, whereas 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 downregulated in wild-type cells. These results indicate that MMP10 serves a beneficial role in response to acute infection by moderating the proinflammatory response of resident and infiltrating macrophages.
Center for Lung Biology, University of Washington, Seattle, WA 98109; Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105;
Ryan S
0000-0003-3489-6127
RS
McMahan
Center for Lung Biology, University of Washington, Seattle, WA 98109; Department of Medicine, University of Washington, Seattle, WA 98195;
Timothy P
TP
Birkland
Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048; and.
Kate S
KS
Smigiel
Center for Lung Biology, University of Washington, Seattle, WA 98109; Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105; Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048; and.
Tyler C
0000-0003-0475-2923
TC
Vandivort
Center for Lung Biology, University of Washington, Seattle, WA 98109; Department of Medicine, University of Washington, Seattle, WA 98195; Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048; and.
Maryam G
MG
Rohani
Center for Lung Biology, University of Washington, Seattle, WA 98109; Department of Medicine, University of Washington, Seattle, WA 98195;
Anne M
AM
Manicone
Center for Lung Biology, University of Washington, Seattle, WA 98109; Department of Pediatrics, University of Washington, Seattle, WA 98195.
John K
0000-0001-6106-8349
JK
McGuire
Center for Lung Biology, University of Washington, Seattle, WA 98109; Department of Medicine, University of Washington, Seattle, WA 98195;
Sina A
SA
Gharib
Center for Lung Biology, University of Washington, Seattle, WA 98109; Department of Medicine, University of Washington, Seattle, WA 98195; Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048; and bill.parks@cshs.org.
William C
WC
Parks
D019264:Adoptive Transfer; D000818:Animals; D003550:Cystic Fibrosis / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007249:Inflammation / Q000276:immunology*; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D008297:Male; D053506:Matrix Metalloproteinase 10 / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011552:Pseudomonas Infections / Q000276:immunology
D053506:Matrix Metalloproteinase 10