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

Fernando Cruz-Guilloty, Ali M. Saeed, Stephanie Duffort, Marisol Cano, Katayoon B. Ebrahimi, Asha Ballmick, Yaohong Tan, Hua Wang, James M. Laird, Robert G. Salomon, James T. Handa, Victor L. Perez

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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, interferongamma (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.

Original languageEnglish (US)
Article numbere88201
JournalPloS one
Volume9
Issue number2
DOIs
StatePublished - Feb 19 2014

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Cruz-Guilloty, F., Saeed, A. M., Duffort, S., Cano, M., Ebrahimi, K. B., Ballmick, A., Tan, Y., Wang, H., Laird, J. M., Salomon, R. G., Handa, J. T., & Perez, V. L. (2014). T cells and macrophages responding to oxidative damage cooperate in pathogenesis of a mouse model of age-related macular degeneration. PloS one, 9(2), [e88201]. https://doi.org/10.1371/journal.pone.0088201