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Blood, 15 October 2008, Vol. 112, No. 8, pp. 3455-3464. Prepublished online as a Blood First Edition Paper on July 25, 2008; DOI 10.1182/blood-2007-12-129080. This Article Full Text (PDF) All Versions of this Article: blood-2007-12-129080v1 112/8/3455    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Dean, R. A Articles by Overall, C. M Search for Related Content PubMed PubMed Citation Articles by Dean, R. A Articles by Overall, C. M Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 17, 2007 Accepted June 24, 2008 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 PMN influx Richard A Dean, Jennifer H Cox, Caroline L Bellac, Alain Doucet, Amanda E Starr, and Christopher M Overall* Centre For Blood Research, University of British Columbia, Vancouver, Canada * Corresponding author; email: chris.overall{at}ubc.ca. Through the activity of macrophage-specific matrix metalloproteinase (MMP)-12 we found that macrophages dampen the LPS-induced influx of polymorphonuclear leukocytes (PMNs)- so 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, carboxy-terminal to it. Murine (m) MMP-12 also cleaves mCXCL1, 2, and 3 at E-LR. MMP-12-cleaved mCXCL2 (MIP-2) and mCXCL3 (DCIP) 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 h after intranasal instillation of LPS in Mmp12-/- mice compared to wild-types. Specificity occurred at two levels. Macrophage MMP-1 and MMP-9 did not cleave in the ELR motif. Second, unlike human ELR+CXC chemokines, mCXCL5 (LIX) was not inactivated. Rather, mMMP-12 cleavage at Ser4-Val5 activated the chemokine promoting enhanced PMN early infiltration in wild-type mice compared to Mmp12-/- mice 8 h after LPS-challenge in air pouches. We propose the macrophage, specifically through MMP-12, assists in orchestrating the regulation of acute inflammatory responses by precise proteolysis of ELR+CXC and CC chemokines. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: I. Vanlaere and C. Libert Matrix Metalloproteinases as Drug Targets in Infections Caused by Gram-Negative Bacteria and in Septic Shock Clin. Microbiol. Rev., April 1, 2009; 22(2): 224 - 239. [Abstract] [Full Text] [PDF]

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