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Sijia Cao, Jiangyuan Gao, Jing Z. Cui, Kailun Jiang, Eleanor To, Dean Zhang, Valerie A. White, Joanne A. Matsubara; Localization of Inflammatory Cytokines in Human Eyes with AMD. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1663.
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© ARVO (1962-2015); The Authors (2016-present)
Earlier in vitro studies identified several inflammatory modulators upregulated after stimulation of RPE cells with either amyloid beta (Aβ) or advanced glycation end products, two known components of drusen. Our earlier findings suggest that drusen may induce inflammatory cytokine overexpression in RPE, and thus promote AMD disease progression. The purpose of this study is to examine the cellular localization of inflammatory cytokines in the outer retina of the human AMD eye.
Six AMD (4 exudative and 2 atrophic) and 30 normal post-mortem eyes were consented for research, embedded in paraffin and processed for immunohistochemistry using antibodies against five proteins of interest from our earlier studies: amyloid precursor protein (APP), interleukin 1beta (IL-1β), CXCL11, interleukin 1 receptor antagonist (IL-1ra), and interleukin 10 (IL-10). Control sections were run using a non-immune IgG at the same concentration as the primary antibody.
APP was strongly expressed in the cytoplasm of RPE cells in close proximity to drusen sites in the AMD eye (e.g. distance of <10 RPE cell diameters). IL-1β, a proinflammatory cytokine, was also expressed in cytoplasm of RPE cells in close proximity to drusen, as well as in the drusen sites themselves in the AMD eye. CXCL11 was expressed in drusen, choroid and Bruch’s membrane of the exudative, but not the atrophic, AMD eye. IL-10, an anti-inflammatory cytokine, was strongly expressed in drusen and choroid of the AMD eye. IL-1ra, another inhibitor of inflammation, was expressed in RPE and choroid in AMD eyes. In normal eyes, IL-1ra was strongly expressed in eyes with drusen (vs eyes without drusen) and in the peripheral (vs macular) retina.
Our study demonstrated a unique pattern of immunoreactivity associated with the human AMD eye that is consistent with our earlier in vitro stimulation studies on RPE cells. The presence of APP in RPE cells in close proximity to drusen, may suggest that Aβ, an APP cleavage product found in drusen, might originate from RPE dysfunction. Interestingly, both proinflammatory and inhibitors of inflammation appear to be highly expressed in RPE cells near drusen sites. While often considered a consequence of the disease process, our data suggest that drusen may promote AMD progression by proinflammatory mechanisms.
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