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.
Lin
Michelle
M
Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106-7286, USA.
Jackson
Patricia
P
Tester
Angus M
AM
Diaconu
Eugenia
E
Overall
Christopher M
CM
Blalock
J Edwin
JE
Pearlman
Eric
E
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