title: T cells and macrophages responding to oxidative damage cooperate in pathogenesis of a mouse model of age-related macular degeneration.
abstract: Age-related macular degeneration (AMD) is a major disease affecting central vision, but the pathogenic mechanisms are not fully understood. Using a mouse model, we examined the relationship of two factors implicated in AMD development: oxidative stress and the immune system. Carboxyethylpyrrole (CEP) is a lipid peroxidation product associated with AMD in humans and AMD-like pathology in mice. Previously, we demonstrated that CEP immunization leads to retinal infiltration of pro-inflammatory M1 macrophages before overt retinal degeneration. Here, we provide direct and indirect mechanisms for the effect of CEP on macrophages, and show for the first time that antigen-specific T cells play a leading role in AMD pathogenesis. In vitro, CEP directly induced M1 macrophage polarization and production of M1-related factors by retinal pigment epithelial (RPE) cells. In vivo, CEP eye injections in mice induced acute pro-inflammatory gene expression in the retina and human AMD eyes showed distinctively diffuse CEP immunolabeling within RPE cells. Importantly, interferon-gamma (IFN-γ) and interleukin-17 (IL-17)-producing CEP-specific T cells were identified ex vivo after CEP immunization and promoted M1 polarization in co-culture experiments. Finally, T cell immunosuppressive therapy inhibited CEP-mediated pathology. These data indicate that T cells and M1 macrophages activated by oxidative damage cooperate in AMD pathogenesis.
authors.affiliation: Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida, United States of America ; Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Fernando
authors.initials: F
authors.lastname: Cruz-Guilloty
authors.affiliation: Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Ali M
authors.initials: AM
authors.lastname: Saeed
authors.affiliation: Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Duffort
authors.affiliation: Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Marisol
authors.initials: M
authors.lastname: Cano
authors.affiliation: Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Katayoon B
authors.initials: KB
authors.lastname: Ebrahimi
authors.affiliation: Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Asha
authors.initials: A
authors.lastname: Ballmick
authors.affiliation: Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Yaohong
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Department of Chemistry, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: James M
authors.initials: JM
authors.lastname: Laird
authors.affiliation: Department of Chemistry, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Salomon
authors.affiliation: Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: James T
authors.initials: JT
authors.lastname: Handa
authors.affiliation: Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida, United States of America ; Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Victor L
authors.initials: VL
authors.lastname: Perez
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007114:Immunization; D007371:Interferon-gamma / Q000096:biosynthesis; D015851:Interleukin-7 / Q000096:biosynthesis; D008264:Macrophages / Q000166:cytology* / Q000276:immunology*; D008268:Macular Degeneration / Q000209:etiology* / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000276:immunology*; D011758:Pyrroles / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*
chemical_list: D015851:Interleukin-7; D011758:Pyrroles; D007371:Interferon-gamma; D016572:Cyclosporine; D020123:Sirolimus