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Inflammatory Mediators Induced by Amyloid-Beta in the Retina and RPE in vivo: Implications for Inflammasome Activation in Age-Related Macular Degeneration.
Liu RT, Gao J, Cao S, Sandhu N, Cui JZ, Chou CL, Fang E, Matsubara JA
Abstract:
PURPOSE:
Drusen are hallmarks of age-related macular degeneration (AMD). Amyloid beta 1-40 (Aβ 1-40), a constituent of drusen, is known to stimulate inflammatory pathways in RPE, however, its effect in vivo is not known. The purpose of this study is to examine the effect of Aβ 1-40 on cytokine expression and inflammasome activation relevant to AMD in an animal model.
METHODS:
Wild-type rats received intravitreal injections of Aβ 1-40 and eyes were taken from Day 1, 4, 14 and 49 post-injection. The RPE, neuroretina and vitreous were analyzed for cytokine expression, inflammasome activation, and microglial response via RT-PCR, immunohistochemistry and suspension array assay. Retinal cell loss was assessed via apoptotic markers and retinal thickness.
RESULTS:
Aβ 1-40 stimulated upregulation of IL-6, TNF-α, IL-1β, IL-18, caspase-1, NLRP3 and XAF1 genes in the RPE/choroid and the neuroretina. Increased IL-1β and IL-6 immunoreactivity was found in retinal sections and elevated levels of IL-1β and IL-18 in the vitreous of Aβ-injected eyes. Aβ 1-40 induced a moderate increase in CD11b/c-reactive cells on Day 1 post-injection only. No evidence of the pro-apoptotic XAF1 protein, p53, TUNEL, or retinal thinning was observed.
CONCLUSION:
These results confirm earlier in vitro work and support the pro-inflammatory role of drusen component Aβ 1-40 in the RPE and retina. Inflammasome activation may be responsible for this effect in vivo. This model is useful to understand cellular triggers of inflammasome activation and proposed early inflammatory events in the outer retina associated with the etiology of AMD.
Drusen are hallmarks of age-related macular degeneration (AMD). Amyloid beta 1-40 (Aβ 1-40), a constituent of drusen, is known to stimulate inflammatory pathways in RPE, however, its effect in vivo is not known. The purpose of this study is to examine the effect of Aβ 1-40 on cytokine expression and inflammasome activation relevant to AMD in an animal model.
METHODS:
Wild-type rats received intravitreal injections of Aβ 1-40 and eyes were taken from Day 1, 4, 14 and 49 post-injection. The RPE, neuroretina and vitreous were analyzed for cytokine expression, inflammasome activation, and microglial response via RT-PCR, immunohistochemistry and suspension array assay. Retinal cell loss was assessed via apoptotic markers and retinal thickness.
RESULTS:
Aβ 1-40 stimulated upregulation of IL-6, TNF-α, IL-1β, IL-18, caspase-1, NLRP3 and XAF1 genes in the RPE/choroid and the neuroretina. Increased IL-1β and IL-6 immunoreactivity was found in retinal sections and elevated levels of IL-1β and IL-18 in the vitreous of Aβ-injected eyes. Aβ 1-40 induced a moderate increase in CD11b/c-reactive cells on Day 1 post-injection only. No evidence of the pro-apoptotic XAF1 protein, p53, TUNEL, or retinal thinning was observed.
CONCLUSION:
These results confirm earlier in vitro work and support the pro-inflammatory role of drusen component Aβ 1-40 in the RPE and retina. Inflammasome activation may be responsible for this effect in vivo. This model is useful to understand cellular triggers of inflammasome activation and proposed early inflammatory events in the outer retina associated with the etiology of AMD.
