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VL Perez; Membrane Fas Ligand Induces While Soluble Fas Ligand Blocks Neutrophil Medicated Inflammation, Apoptosis and Scar Formation in the Cornea Stroma . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1951.
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Purpose: Fas Ligand (FasL) is found in two forms: soluble and membrane bound. We have previously shown that the selective expression of membrane FasL (mFasL) in the cornea induces inflammation, while soluble (sFasL) is anti-inflammatory. We believe that the induction of mFasL keratitis is dependent on the recruitment of neutrophils into the cornea and that sFasL prevents this process. Methods: Membrane and soluble FasL were expressed in the corneal stroma of C57BL/6 mice by naked DNA transfection using intra-stromal injection of (5ug total) cDNA constructs. These cDNAs were expressed in a plasmid containing the CMV promoter and a GFP marker. Gene expression was confirmed by measuring in vivo GFP expression in the cornea with fluorescent microscopy. To induce the recruitment of neutrophils into the cornea, the central corneal epithelium was removed 24 hrs after gene transfection and corneal inflammation was observed by slit-lamp examination and histological analysis. Results: Expression of mFasL in the corneal stroma induces scar formation by days 10-15 in the absence of keratitis. However, if mFasL positive corneas are injured with epithelial scraping, keratitis is induced between days 3-7. Corneas expressing either sFasL or the control vector did not develop either keratitis, or corneal scarring. Histological analysis of mFasL induced keratitis, revealed areas of cellular apoptosis, associated with an exuberant accumulation of neutrophils and macrophages in the corneal stroma 24 hrs after epithelial scraping. The mFasL induced corneal scarring was associated with the presence of scattered neutrophils surrounding areas of stromal thickening. No evidence of apoptosis or neutrophils infiltration was seen in corneas expressing sFasL. Conclusion: The presence of mFasL in the corneal stroma induces apoptosis, scar formation and keratitis, if neutrophils are recruited by epithelial injury. Corneas expressing sFasL are protected against inflammation and scar formation. Our data implies the cornea uses sFasL to down-regulate innate immunity.
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