Matrix metalloproteinase-8 facilitates neutrophil migration through the corneal stromal matrix by collagen degradation and production of the chemotactic peptide Pro-Gly-Pro

Am J Pathol. 2008 Jul;173(1):144-53. doi: 10.2353/ajpath.2008.080081. Epub 2008 Jun 13.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Chemokines, CXC / biosynthesis
  • Collagen / metabolism*
  • Corneal Stroma / immunology
  • Corneal Stroma / metabolism*
  • Corneal Stroma / pathology
  • Electrophoresis, Polyacrylamide Gel
  • Female
  • Immunohistochemistry
  • Inflammation / metabolism
  • Inflammation / pathology
  • Keratitis / immunology
  • Keratitis / metabolism*
  • Keratitis / pathology
  • Lipopolysaccharides / toxicity
  • Matrix Metalloproteinase 8 / metabolism*
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Neutrophil Infiltration / physiology*
  • Oligopeptides / biosynthesis*
  • Proline / analogs & derivatives*
  • Proline / biosynthesis
  • Receptors, Interleukin-8B / deficiency


  • Chemokines, CXC
  • Lipopolysaccharides
  • Oligopeptides
  • Receptors, Interleukin-8B
  • prolyl-glycyl-proline
  • Collagen
  • Proline
  • Matrix Metalloproteinase 8
  • Matrix Metalloproteinase 9