T cells and macrophages responding to oxidative damage cooperate in pathogenesis of a mouse model of age-related macular degeneration

• Published in: PloS one 2014-02, Vol.9 (2), p.e88201-e88201
• Main Authors: Cruz-Guilloty, Fernando, Saeed, Ali M, Duffort, Stephanie, Cano, Marisol, Ebrahimi, Katayoon B, Ballmick, Asha, Tan, Yaohong, Wang, Hua, Laird, James M, Salomon, Robert G, Handa, James T, Perez, Victor L
• Format: Article
• Language: English
• Subjects: Age; Age related diseases; Angiogenesis; Animals; Antigens; Atherosclerosis; B cells; Biological Transport - drug effects; Biology; Cell culture; Cyclosporine - pharmacology; Cytokines; Disease; Disease Models, Animal; Eye (anatomy); Female; Gene expression; Humans; Immune system; Immunization; Immunology; Immunosuppressive agents; Immunotherapy; Infiltration; Inflammation; Interferon; Interferon-gamma - biosynthesis; Interleukin 17; Interleukin-7 - biosynthesis; Interleukins; Lipid peroxidation; Lymphocytes; Lymphocytes T; Macrophages; Macrophages - cytology; Macrophages - immunology; Macular degeneration; Macular Degeneration - etiology; Macular Degeneration - immunology; Macular Degeneration - metabolism; Male; Medicine; Mice; Oxidative stress; Oxidative Stress - immunology; Pathogenesis; Pathology; Peroxidation; Photoreceptors; Polarization; Pyrroles - metabolism; Retina; Retinal degeneration; Retinal Pigment Epithelium - drug effects; Retinal Pigment Epithelium - immunology; Retinal Pigment Epithelium - metabolism; Sirolimus - pharmacology; T cells; T-Lymphocytes - cytology; T-Lymphocytes - immunology; Tumor necrosis factor-TNF; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0088201

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.