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* School of Anatomy and Human Biology and the Lions Eye Institute, The University of Western Australia, Crawley, Western Australia, Australia;
Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, 44106;
Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602; and
Department of Ophthalmology, Bascom Palmer Eye Institute, Miami, FL 33136
The mammalian cornea contains an extensive network of resident macrophages and dendritic cells. To determine the role of these cells in LPS-induced corneal inflammation, TLR4–/– mice were sublethally irradiated and reconstituted with bone marrow cells from either enhanced GFP (eGFP)+/C57BL/6 or eGFP+/TLR4–/– mice. The corneal epithelium was abraded, LPS was added topically, and cellular infiltration to the corneal stroma and development of corneal haze were examined after 24 h. TLR4–/– mice reconstituted with C57BL/6, but not TLR4–/– bone marrow cells donor cells were found to cause infiltration of eGFP+ cells to the cornea, including neutrophils, and also increased corneal haze compared with saline-treated corneas. In a second experimental approach, corneas of transgenic macrophage Fas induced apoptosis (Mafia) mice were stimulated with LPS. These mice express eGFP and a suicide gene under control of the c-fms promoter, and systemic treatment with the FK506 dimerizer (AP20187) causes Fas-mediated apoptosis of monocytic cells. AP20187-treated mice had significantly fewer eGFP+ cells in the cornea than untreated mice. After stimulation with LPS neutrophil recruitment and development of corneal haze were impaired in AP20187-treated mice compared with untreated controls. Furthermore, LPS induced CXCL1/KC and IL-1
production within 4 h in corneas of untreated Mafia mice, which is before cellular infiltration; however, cytokine production was impaired after AP20187 treatment. Together, results from both experimental approaches demonstrate an essential role for resident corneal monocytic lineage cells (macrophages and dendritic cells) in development of corneal inflammation.
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1 This work was supported by the National Institute of Health Grants R01EY14362 (to E.P.) EY11373 (Core grant, to E.P.), and K08 EY014912 (to V.L.P.). Additional support for these studies was provided by The Research to Prevent Blindness Foundation and the Ohio Lions Eye Research Foundation.
2 H.R.C., E.C.C., and Y.S. contributed equally to the current study.
3 Address correspondence and reprint requests to Dr. Eric Pearlman, Department of Ophthalmology and Visual Sciences, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106. E-mail address: Eric.Pearlman{at}case.edu
4 Abbreviations used in this paper: DC, dendritic cell; Mafia, macrophage Fas-induced apoptosis; eGFP, enhanced GFP; HBSS, Hanks’ buffered salt solution.
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  K. Gentil and E. Pearlman Gamma Interferon and Interleukin-1 Receptor 1 Regulate Neutrophil Recruitment to the Corneal Stroma in a Murine Model of Onchocerca volvulus Keratitis Infect. Immun., April 1, 2009; 77(4): 1606 - 1612. [Abstract] [Full Text] [PDF]
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