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J. Biol. Chem., Vol. 282, Issue 49, 35502-35509, December 7, 2007

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Keratocan and Lumican Regulate Neutrophil Infiltration and Corneal Clarity in Lipopolysaccharide-induced Keratitis by Direct Interaction with CXCL1^*

Eric C. Carlson¹, Michelle Lin, Chia-Yang Liu, Winston W-Y. Kao, Victor L. Perez^¶, and Eric Pearlman

From the Department of Ophthalmology, Case Western Reserve University, Cleveland, Ohio 44106, Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio 45267, and ^¶Department of Ophthalmology, University of Miami, Miami, Florida 33136

Keratocan and lumican are keratan-sulfate proteoglycans (KSPG), which have a critical role in maintaining corneal clarity. To determine whether these KSPGs have a role in corneal inflammation, we examined Kera^–/– and Lum^–/– mice in a model of lipopolysaccharide (LPS)-induced keratitis in which wild-type mice develop increased corneal thickness and haze due to neutrophil infiltration to the corneal stroma. Corneal thickness increases caused by LPS mice were significantly lower in Kera^–/– and Lum^–/– than wild-type mice. Further, LPS-injected Lum^–/– mice had elevated corneal haze levels compared with that of Kera^–/– and wild-type. At 24 h post-injection, total enhanced green fluorescent protein-positive bone marrow-derived inflammatory cells in chimeric mice was significantly lower in Kera^–/– mice and Lum^–/– mice compared with wild-type mice. Neutrophil infiltration was inhibited in Kera^–/– and Lum^–/– mice at 6 and 24 h post-stimulation, with Lum^–/– corneas having the most profound defect in neutrophil migration. Reconstitution of keratocan and lumican expression in corneas of Kera^–/– and Lum^–/– mice using adeno-keratocan and adeno-lumican viral vectors, respectively, resulted in normal neutrophil infiltration in response to LPS. Immunoprecipitation/Western blot analysis showed that lumican and keratocan core proteins bind the CXC chemokine KC during a corneal inflammatory response, indicating that corneal KSPGs mediate neutrophil recruitment to the cornea by regulating chemokine gradient formation. Together, these data support a significant role for lumican and keratocan in a corneal inflammatory response with respect to edema, corneal clarity, and cellular infiltration.

Received for publication, July 16, 2007 , and in revised form, October 1, 2007.

^* This work was supported by National Institutes of Health Grants EY10320 and EY11373 (to E. P.), EY11845 (to W. W. K.), and K08 EY014912 (to V. L. P.), NEI, National Institutes of Health Grant RO1 12486 (to C. Y. L.), the Research to Prevent Blindness Foundation, and Ohio Lions Eye Research Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Ophthalmology and Visual Sciences, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106-7286. Fax: 216-368-3713; E-mail: Eric.Carlson{at}case.edu.

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