Published online before print June 13, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: ajpath.2008.080081v1 173/1/144    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Lin, M. Articles by Pearlman, E. PubMed PubMed Citation Articles by Lin, M. Articles by Pearlman, E.

(American Journal of Pathology. 2008;173:144-153.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080081

Matrix Metalloproteinase-8 Facilitates Neutrophil Migration through the Corneal Stromal Matrix by Collagen Degradation and Production of the Chemotactic Peptide Pro-Gly-Pro

Michelle Lin^*, Patricia Jackson, Angus M. Tester, Eugenia Diaconu^*, Christopher M. Overall, J. Edwin Blalock and Eric Pearlman^*

From the Department of Ophthalmology and Visual Sciences,^* Case Western Reserve University, Cleveland, Ohio; the Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama; and the Center for Blood Research, and Departments of Oral Biological and Medical Sciences, and Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada

Matrix metalloproteinase (MMP)-8 and MMP-9 play several roles in inflammation, including degradation of extracellular matrix (ECM) components and regulation of cytokine activity. To determine the roles of MMP-8 and MMP-9 in a neutrophil-dependent inflammatory response, we used a murine model of corneal inflammation in which LPS is injected into the corneal stroma. In contrast to wild-type mice, we found that i) lipopolysaccharide (LPS)-injected CXCR2^–/– corneas had impaired neutrophil infiltration and did not express either MMP-8 or MMP-9; ii) neutrophil migration through the central cornea was impaired in Mmp8^–/–, but not Mmp9^–/–, mice; iii) neutrophil migration was inhibited in collagenase-resistant mice; iv) the chemotactic Pro-Gly-Pro (PGP) tripeptide that binds CXCR2 was decreased in CXCR2^–/– mice; v) PGP production was impaired in Mmp8^–/– corneas; and vi) neutralizing anti-PGP antibody did not inhibit neutrophil infiltration in Mmp8^–/– mice. We found no effects of MMP-8 on LPS-induced CXC chemokine (LIX, or CXCL5)-induced neutrophil recruitment or on LPS-induced CXC chemokine production. Together, these studies indicate that neutrophils contribute to the production of both MMP-8 and MMP-9 in LPS-injected corneas and that MMP-8 regulates neutrophil migration through the dense collagenous ECM of the corneal stroma by generating chemotactic PGP during inflammation.