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Paul Luke Ibbett, Andrew J Lotery, V. Hugh Perry, Jessica Teeling; The impact of systemic inflammation on age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):848.
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Systemic inflammation exacerbates neurodegenerative diseases e.g. Alzheimer’s disease, but the impact of systemic inflammation on age-related macular degeneration (AMD) is unknown. We hypothesise that a) systemic inflammation can activate and ‘prime’ retinal microglia to respond in a greatly exaggerated manner to subsequent immune activation and b) that this contributes to AMD pathogenesis and/or progression. We tested this hypothesis by modelling inflammatory drusen in AMD using immune complexes and chronic systemic inflammation using bacterial infection.
Mice received an i.p. injection of Salmonella Typhimurium (S. Typhimurium) or saline and were perfused with heparinised saline 7 and 28 days post infection (n=5 per group). Retinal tissue was snap frozen and stored at -80°C until qPCR analysis of GADPH and IL-1β mRNA levels. Whole eyes were embedded in OCT and stored at -20°C until cryosectioned and assessed for DAB immunoreactivity to microglial markers CD11b, FcγRI and MHCII. To test for priming, mice received an i.p. injection of S. Typhimurium followed 28 days later by i.p. injection of LPS (0.5mg/kg) or saline (n=5 per group) and tissue was collected 24 hours later and examined as before. Immune complexes were formed in the retinae of mice as previously described (Murinello et al. 2014) followed 28 days later by i.p. injection of S. Typhimurium (n=3 per group). Tissue was collected 7 days later and examined as before.
7 days of S. Typhimurium infection induced MHCII expression associated with retinal blood vessels. Retinal IL-1β mRNA expression was undetectable in saline controls and detectable after 28 days of S. Typhimurium infection. LPS injection, induced a threefold increase in IL-1β mRNA in the retina after 24hrs in S. Typhimurium infected animals (p<0.05; Two-tailed T test), but not saline or LPS only controls. CD11b, FcγRI and MHCII expression in the retina after 7 days of S. Typhimurium infection was not increased by previous immune complex induced retinal inflammation.
Chronic systemic inflammation induced blood-retinal-barrier activation after 7 days and microglial activation and IL-1β expression in the retina after 28 days. These microglia are primed to respond in an exaggerated manner to subsequent inflammatory stimuli. This may contribute to the pathogenesis of AMD, if microglia are primed by systemic inflammation to respond to inflammatory drusen formation in AMD.
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