Journal
PLOS ONE
Volume 9, Issue 2, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0088201
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Funding
- Edward N. & Della L. Thome Memorial Foundation Bank of America N.A. Trustee Award Program in Macular Degeneration Research
- NIH [P30EY14801]
- Prevent Blindness (Unrestricted Grant to the Bascom Palmer Eye Institute) [NIH R01-GM21249, NIH EY14005, EY019904]
- RPB Senior Scientist Award
- Sheila and David Fuente Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center
- Howard Hughes Medical Institute Fellowship of the Life Sciences Research Foundation
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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-gamma ) 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.
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