title: Regulation of corneal inflammation by neutrophil-dependent cleavage of keratan sulfate proteoglycans as a model for breakdown of the chemokine gradient.
abstract: Keratocan and lumican are small, leucine-rich repeat KSPGs in the extracellular matrix (ECM) of the mammalian cornea, whose primary role is to maintain corneal transparency. In the current study, we examined the role of these proteoglycans in the breakdown of the chemokine gradient and resolution of corneal inflammation. LPS was injected into the corneal stroma of C57BL/6 mice, and corneal extracts were examined by immunoblot analysis. We found reduced expression of the 52-kD keratocan protein after 6 h and conversely, increased expression of 34/37 kD immunoreactive products. Further, appearance of the 34/37-kD proteins was dependent on neutrophil infiltration to the cornea, as the appearance of these products was coincident with neutrophil infiltration, and the 34/37-kD products were not detected in explanted corneas or in CXCR2(-/-) corneas with deficient neutrophil recruitment. Furthermore, the 34/37-kD products and CXCL1/KC were detected in the anterior chamber, into which the corneal stroma drains; and CXCL1/KC was elevated significantly in keratocan(-/-) and lumican(-/-) mice. Together, these findings indicate that the inflammatory response in the cornea is regulated by proteoglycan/CXCL1 complexes, and their diffusion into the anterior chamber is consistent with release of a chemokine gradient and resolution of inflammation.
authors.affiliation: Case Comprehensive Cancer Center, National Center for Regenerative Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Carlson
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.forename: Jeffery
authors.initials: J
authors.lastname: Auletta
authors.forename: Winston W-Y
authors.initials: WW
authors.lastname: Kao
authors.forename: Chia-Yang
authors.initials: CY
authors.lastname: Liu
authors.forename: Victor L
authors.initials: VL
authors.lastname: Perez
authors.forename: Eric
authors.initials: E
authors.lastname: Pearlman
mesh_terms: D000818:Animals; D000867:Anterior Chamber / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D054360:Chemokine CXCL1 / Q000096:biosynthesis; D018925:Chemokines / Q000378:metabolism*; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D003315:Cornea / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D003319:Corneal Stroma / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D007632:Keratan Sulfate / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D000071234:Lumican; D051379:Mice; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011509:Proteoglycans / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000172:deficiency / Q000378:metabolism
chemical_list: D054360:Chemokine CXCL1; D018925:Chemokines; D011508:Chondroitin Sulfate Proteoglycans; C099280:Kera protein, mouse; D008070:Lipopolysaccharides; C000604307:Lum protein, mouse; D000071234:Lumican; D011509:Proteoglycans; D023063:Receptors, Interleukin-8B; D007632:Keratan Sulfate