Published online before print June 13, 2008

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(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.

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