Matrix metalloproteinase-8 facilitates neutrophil migration through the corneal stromal matrix by collagen degradation and production of the chemotactic peptide Pro-Gly-Pro.
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.
Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106-7286, USA.
Michelle
M
Lin
Patricia
P
Jackson
Angus M
AM
Tester
Eugenia
E
Diaconu
Christopher M
CM
Overall
J Edwin
JE
Blalock
Eric
E
Pearlman
D000818:Animals; D015153:Blotting, Western; D019743:Chemokines, CXC / Q000096:biosynthesis; D003094:Collagen / Q000378:metabolism*; D003319:Corneal Stroma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007634:Keratitis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020556:Neutrophil Infiltration / Q000502:physiology*; D009842:Oligopeptides / Q000096:biosynthesis*; D011392:Proline / Q000031:analogs & derivatives* / Q000096:biosynthesis; D023063:Receptors, Interleukin-8B / Q000172:deficiency
D019743:Chemokines, CXC; D008070:Lipopolysaccharides; D009842:Oligopeptides; D023063:Receptors, Interleukin-8B; C113164:prolyl-glycyl-proline; D003094:Collagen; D011392:Proline; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9