TY - JOUR
T1 - T cells and macrophages responding to oxidative damage cooperate in pathogenesis of a mouse model of age-related macular degeneration
AU - Cruz-Guilloty, Fernando
AU - Saeed, Ali M.
AU - Duffort, Stephanie
AU - Cano, Marisol
AU - Ebrahimi, Katayoon B.
AU - Ballmick, Asha
AU - Tan, Yaohong
AU - Wang, Hua
AU - Laird, James M.
AU - Salomon, Robert G.
AU - Handa, James T.
AU - Perez, Victor L.
PY - 2014/2/19
Y1 - 2014/2/19
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84896111012&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84896111012&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0088201
DO - 10.1371/journal.pone.0088201
M3 - Article
C2 - 24586307
AN - SCOPUS:84896111012
SN - 1932-6203
VL - 9
JO - PloS one
JF - PloS one
IS - 2
M1 - e88201
ER -