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Xavier P Guillonneau, shulong hu, Bertrand Calippe, Sophie Lavalette, Jose Alain Sahel, Florian Sennlaub; Intravitreal injection of a P2RX7 antagonist reduces photoreceptor cell death in a model of subretinal inflammation. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):844.
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Inflammatory mononuclear phagocytes (MP) accumulate in geographic atrophy form of age related macular degeneration (AMD). We have previously shown that Cx3cr1-deficient mice develop age- and light-induced subretinal accumulation of MP that is responsible for photoreceptor degeneration. The mechanisms by which MP accumulation leads to degeneration remains unknown. Cx3cr1-deficient MP have been shown to lead to increased neuronal apoptosis through IL-1beta (IL-1β) secretion in the brain. To test whether reducing IL1 B secretion by antagonizing P2XR7 reduces photoreceptor toxicity, we injected brilliant blue G (BBG) in the vitreous of mice subjected to a light stress.
Mice were submitted to 4 days of light challenge to allow for subretinal inflammation and returned to normal cyclic light conditions. Mice received an intravitreal injection of PBS or BBG at day 3 and day 7. Mice were sacrified at day 5 and 10 and retinal and choroidal flatmounts were evaluated for P2RX7 expression, MP accumulation and TUNEL staining. Photoreceptor degeneration was evaluated at day 21 on historesin section.
Immunohistochemistry of P2XR7 on Cx3cr1GFP/GFP mice light-challenged retinal flatmounts showed that P2RX7 expression was restricted to MP that had infiltrated the subretinal space while IBA1+. Microglial cells of the inner retina were not P2RX7 positive. Quantification of subretinal MP on IBA1 stained choiroidal and retinal flamounts stained at d10 did not reveal any differences in subretinal MP accumulation after BBG injections. In contrast, TUNEL staining of apoptotic nuclei in the ONL of retinal flatmounts showed a two fold decreased in the number of apoptotic photoreceptor cells in animal treated with BBG correlated with an increased in the ONL thickness at d21.
Our results demonstrate P2RX7 inhibition reduces subretinal MP toxicity in a model of light-induced subretinal inflammation and suggest that intravitreal injections of P2RX7 antagonists might help at preventing photoreceptor cell loss in AMD.
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