title: MMP28 promotes macrophage polarization toward M2 cells and augments pulmonary fibrosis.
abstract: Members of the MMP family function in various processes of innate immunity, particularly in controlling important steps in leukocyte trafficking and activation. MMP28 (epilysin) is a member of this family of proteinases, and we have found that MMP28 is expressed by macrophages and regulates their recruitment to the lung. We hypothesized that MMP28 regulates other key macrophage responses, such as macrophage polarization. Furthermore, we hypothesized that these MMP28-dependent changes in macrophage polarization would alter fibrotic responses in the lung. We examined the gene expression changes in WT and Mmp28-/- BMDMs, stimulated with LPS or IL-4/IL-13 to promote M1 and M2 cells, respectively. We also collected macrophages from the lungs of Pseudomonas aeruginosa-exposed WT and Mmp28-/- mice to evaluate changes in macrophage polarization. Lastly, we evaluated the macrophage polarization phenotypes during bleomycin-induced pulmonary fibrosis in WT and Mmp28-/- mice and assessed mice for differences in weight loss and total collagen levels. We found that MMP28 dampens proinflammatory macrophage function and promots M2 programming. In both in vivo models, we found deficits in M2 polarization in Mmp28-/- mice. In bleomycin-induced lung injury, these changes were associated with reduced fibrosis. MMP28 is an important regulator of macrophage polarization, promoting M2 function. Loss of MMP28 results in reduced M2 polarization and protection from bleomycin-induced fibrosis. These findings highlight a novel role for MMP28 in macrophage biology and pulmonary disease.
authors: *Center for Lung Biology, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington, USA
authors: Sina A
authors: SA
authors: Gharib
authors: *Center for Lung Biology, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington, USA
authors: Laura K
authors: LK
authors: Johnston
authors: †Division of Pulmonary and Critical Care Medicine, Texas Tech University Health Science Center, Lubbock, Texas, USA
authors: Isham
authors: I
authors: Huizar
authors: *Center for Lung Biology, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington, USA
authors: Timothy P
authors: TP
authors: Birkland
authors: *Center for Lung Biology, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington, USA
authors: Josiah
authors: J
authors: Hanson
authors: *Center for Lung Biology, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington, USA
authors: Ying
authors: Y
authors: Wang
authors: *Center for Lung Biology, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington, USA
authors: William C
authors: WC
authors: Parks
authors: *Center for Lung Biology, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington, USA|Correspondence: Center for Lung Biology, Div. of Pulmonary and Critical Care Medicine, University of Washington, 850 Republican Ave., Seattle, WA 98109, USA. E-mail: manicone@uw.edu
authors: Anne M
authors: AM
authors: Manicone
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D016207:Cytokines / Q000494:pharmacology; D004195:Disease Models, Animal; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D053505:Matrix Metalloproteinases, Secreted / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological / Q000235:genetics; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors
chemical_list: D016207:Cytokines; D051193:Toll-Like Receptors; C424663:MMP28 protein, human; D053505:Matrix Metalloproteinases, Secreted
keywords: M1; epilysin; inflammation; monocytes
references: Am J Physiol Lung Cell Mol Physiol. 2003 Aug;285(2):L313-21
references: 12679322
references: Blood. 2002 Aug 15;100(4):1160-7
references: 12149192
references: Am J Respir Cell Mol Biol. 2006 Oct;35(4):466-73
references: 16709958
references: Immunity. 2010 May 28;32(5):593-604
references: 20510870
references: Circ Res. 2013 Feb 15;112(4):675-88
references: 23261783
references: Microsc Microanal. 2012 Feb;18(1):81-90
references: 22153350
references: J Clin Invest. 2005 Jan;115(1):56-65
references: 15630444
references: J Biol Chem. 2001 Mar 30;276(13):10134-44
references: 11121398
references: J Exp Med. 2007 May 14;204(5):1057-69
references: 17485518
references: J Biol Chem. 2001 Nov 23;276(47):43503-8
references: 11571304
references: Biochem J. 2003 Oct 1;375(Pt 1):191-7
references: 12803542
references: Clin Immunol. 2010 Oct;137(1):89-101
references: 20674506
references: Eur Respir Rev. 2012 Jun 1;21(124):152-60
references: 22654088
references: J Mol Cell Cardiol. 2010 Sep;49(3):516-24
references: 20380835
references: Science. 2000 Aug 18;289(5482):1202-6
references: 10947989
references: Int J Biol Sci. 2011;7(9):1273-86
references: 22110380
references: Respir Res. 2011 Oct 31;12:144
references: 22040290
references: Mol Med. 2012 Oct 24;18:1231-9
references: 22777483
references: Am J Physiol Lung Cell Mol Physiol. 2012 Mar 1;302(5):L463-73
references: 22140072
references: Cell. 2002 Nov 27;111(5):635-46
references: 12464176
references: Am J Respir Crit Care Med. 2011 Sep 1;184(5):569-81
references: 21680953
references: Immunity. 2003 Jul;19(1):71-82
references: 12871640
references: Immunity. 2005 Oct;23(4):344-6
references: 16226499
references: Nat Genet. 2000 May;25(1):25-9
references: 10802651
references: Gene. 2001 Sep 5;275(1):185-94
references: 11574168
references: Exp Dermatol. 2008 Nov;17(11):897-907
references: 18803661
references: Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W741-8
references: 15980575
references: J Immunol. 2009 Mar 15;182(6):3866-76
references: 19265166
references: Matrix Biol. 2009 Jun;28(5):263-72
references: 19375502
references: Immunobiology. 2009;214(7):630-41
references: 19264378
references: Am J Respir Cell Mol Biol. 2012 Oct;47(4):417-26
references: 22721830
references: Semin Cell Dev Biol. 2008 Feb;19(1):34-41
references: 17707664
references: Nat Rev Immunol. 2005 Dec;5(12):953-64
references: 16322748