title: Macrophage-specific metalloelastase (MMP-12) truncates and inactivates ELR+ CXC chemokines and generates CCL2, -7, -8, and -13 antagonists: potential role of the macrophage in terminating polymorphonuclear leukocyte influx.
abstract: Through the activity of macrophage-specific matrix metalloproteinase-12 (MMP-12), we found that macrophages dampen the lipopolysaccharide (LPS)-induced influx of polymorphonuclear leukocytes (PMNs)-thus providing a new mechanism for the termination of PMN recruitment in acute inflammation. MMP-12 specifically cleaves human ELR(+) CXC chemokines (CXCL1, -2, -3, -5, and -8) at E-LR, the critical receptor-binding motif or, for CXCL6, carboxyl-terminal to it. Murine (m) MMP-12 also cleaves mCXCL1, -2, and -3 at E-LR. MMP-12-cleaved mCXCL2 (macrophage-inflammatory protein-2 [MIP-2]) and mCXCL3 (dendritic cell inflammatory protein-1 [DCIP-1]) lost chemotactic activity. Furthermore, MMP-12 processed and inactivated monocyte chemotactic proteins CCL2, -7, -8, and -13 at position 4-5 generating CCR antagonists. Indeed, PMNs and macrophages in bronchoalveolar lavage fluid were significantly increased 72 hours after intranasal instillation of LPS in Mmp12(-/-) mice compared with wild type. Specificity occurred at 2 levels. Macrophage MMP-1 and MMP-9 did not cleave in the ELR motif. Second, unlike human ELR(+)CXC chemokines, mCXCL5 (LPS-induced CXC chemokine [LIX]) was not inactivated. Rather, mMMP-12 cleavage at Ser4-Val5 activated the chemokine, promoting enhanced PMN early infiltration in wild-type mice compared with Mmp12(-/-) mice 8 hours after LPS challenge in air pouches. We propose that the macrophage, specifically through MMP-12, assists in orchestrating the regulation of acute inflammatory responses by precise proteolysis of ELR(+)CXC and CC chemokines.
authors.affiliation: Departments ofOral Biological & Medical Sciences, Centre for Blood Research, University of British Columbia, Vancouver, Canada.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Dean
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Cox
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Bellac
authors.forename: Alain
authors.initials: A
authors.lastname: Doucet
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Starr
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Overall
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054410:Chemokine CCL7 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054412:Chemokine CCL8 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019743:Chemokines, CXC / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D018945:Monocyte Chemoattractant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*
chemical_list: C099677:CCL13 protein, human; C111835:CCL2 protein, human; C515450:CCL7 protein, human; C515453:CCL8 protein, human; D018932:Chemokine CCL2; D054410:Chemokine CCL7; D054412:Chemokine CCL8; D019743:Chemokines, CXC; D018945:Monocyte Chemoattractant Proteins; D053508:Matrix Metalloproteinase 12