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E. Carlson, M. Lin, C.-Y. Liu, V. Perez, W. Kao, E. Pearlman; Lumican and Keratocan Regulate Neutrophil Infiltration to the Corneal Stroma in Microbial Keratitis. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3647.
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Keratan-sulfate proteoglycans have an important role in maintaining the uniformity and transparency of the corneal stroma. Inflammation leads to the loss of these two properties initially due to the infiltration of neutrophils. The relationship of lumican and keratocan to neutrophil infiltration was explored during the early stages of keratitis caused by lipolysaccharide (LPS) and microfilaria (river blindness).
LPS and microfilaria-induced keratitis was generated in lumican and keratocan-null mice by intrastromal injection. Neutrophil infiltration was quantitated using NIMP-R14 immunohistochemistry on frozen sections. Moreover, the use of EGFP-bone marrow chimeric lumican and keratocan-null mice (Lum -/- and Kera -/-) were utilized to visualize the infiltration of bone marrow-derived inflammatory cells. Chemokines in the inflamed cornea and anterior chamber were measured using ELISA. Adenoviruses constitutively expressing lumican and keratocan were used to reconstitute the lumican and keratocan-null corneal stroma prior to inflammation.
Lum -/- and Kera -/- mice had a decreased population of neutrophils infiltrating the corneal stroma at 6 and 24 hours post-induction compared with wild-type controls; however, this decrease was more apparent in the lumican-null corneas. Reconstitution of Lum -/- and Kera -/- corneas with adenoviral constructs constitutively expressing lumican and keratocan resulted in a significant increase in the number of neutrophils infiltrating when compared to the adenoviral empty vector confirming the role of these proteins in an innate immune response. The EGFP bone-marrow lumican and keratoan-null chimeric mice reconstituted with wild-type bone marrow cells demonstrated the resident corneal cells were responsible for the phenotype and not the infiltrating cells.
Keratan-sulfate proteoglycans play a critical role in the infiltration of neutrophils to the cornea. Although the actual mechanism of neutrophil inhibition has yet to be determined, previous reports have identified a receptor for lumican as well as its ability to regulate gene expression.
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