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 Handa, Victor L. Perez

Research output: Contribution to journalArticle

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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T-cells
Macrophages
Macular Degeneration
macrophages
pathogenesis
T-lymphocytes
animal models
Immunization
T-Lymphocytes
Retinal Pigments
Pathology
Polarization
Oxidative stress
Interleukin-17
Immune system
Immunosuppressive Agents
Cell culture
Infiltration
Gene expression
immunization

ASJC Scopus subject areas

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

Cite this

T cells and macrophages responding to oxidative damage cooperate in pathogenesis of a mouse model of age-related macular degeneration. / 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; Perez, Victor L.

In: PLoS One, Vol. 9, No. 2, e88201, 19.02.2014.

Research output: Contribution to journalArticle

Cruz-Guilloty, F, Saeed, AM, Duffort, S, Cano, M, Ebrahimi, KB, Ballmick, A, Tan, Y, Wang, H, Laird, JM, Salomon, RG, Handa, J & Perez, VL 2014, 'T cells and macrophages responding to oxidative damage cooperate in pathogenesis of a mouse model of age-related macular degeneration', PLoS One, vol. 9, no. 2, e88201. https://doi.org/10.1371/journal.pone.0088201
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 ; Perez, Victor L. / T cells and macrophages responding to oxidative damage cooperate in pathogenesis of a mouse model of age-related macular degeneration. In: PLoS One. 2014 ; Vol. 9, No. 2.
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