T Cells and Macrophages Responding to Oxidative Damage Cooperate in Pathogenesis of a Mouse Model of Age-Related Macular DegenerationReportar como inadecuado




T Cells and Macrophages Responding to Oxidative Damage Cooperate in Pathogenesis of a Mouse Model of Age-Related Macular Degeneration - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

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.



Autor: Fernando Cruz-Guilloty , Ali M. Saeed, Stephanie Duffort, Marisol Cano, Katayoon B. Ebrahimi, Asha Ballmick, Yaohong Tan, Hua Wan

Fuente: http://plos.srce.hr/



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