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

https://doi.org/10.2353/ajpath.2008.080081Get rights and content

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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This work was supported by the National Institutes of Health (grants EY10320 and EY11373 to E.P., and grants HL077783 and HL090999 to J.E.B.), by the Research to Prevent Blindness (RPB) Foundation and the Ohio Lions Eye Research Foundation, by Prevent Blindness Ohio Foundation (M.L.), and by Cystic Fibrosis Foundation grant R464-CR02 (to J.E.B.). E.P. is also a recipient of an RPB Senior Investigator Award. C.M.O. is supported by a Canada Research Chair in Metalloproteinase Proteomics and Systems Biology, with research grants from the Canadian Institutes of Health Research as well as with a Centre Grant from the Michael Smith Research Foundation. Funds for the purchase of mass spectrometers and the operation of the UAB Mass Spectrometry Shared Facility came from the following NIH grants to U.A.B.: S10 RR19231, P30 CA13148, P50 AT00477, U54 CA100949, P30 AR050948, and P30 DK74038.

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