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Matt Rutar, Rong Xian Chia, Riccardo Natoli, Jan Provis; Chemokine-mediated guidance of the inflammatory response by Müller cells, microglia, and RPE in an animal model of atrophic AMD. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3665.
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Recruitment of inflammatory cells into the injured retina is thought to exacerbate photoreceptor death in retinal degenerations such as age-related macular degeneration (AMD). Monocyte/microglia recruitment is dependent on expression of chemo-attractants, such as chemokines, although their role in AMD is yet to be clarified. Using microarray analysis, we investigate the expression and localization of prominent chemokines and chemokine-regulators in a light-induced model of atrophic AMD.
SD rats were exposed to 1000lx of light for up to 24hrs. At specific time-points during and following exposure, animals were euthanized and retinas processed. Photoreceptor apoptosis was assessed using TUNEL (n=5) and counts were made of monocytes/microglia immunolabeled with IBA1 (n=4 per). Expression of chemokines were assessed by microarray analysis, and qPCR (n=3-4). Some chemokines were also selected for spatiotemporal analysis by in situ hybridization (n=3 per time point). One-way ANOVA was used for statistical analysis.
Using qPCR, significant up-regulation (P<0.05) of chemokines (Ccl3, Ccl4, Ccl7, Cxcl1, Cxcl10, Cxcl11) and chemokine-regulators (Adam17, IL1B, Myd88, Tlr2, Tnfa) was observed at 24hrs, which correlated with the increase (P<0.05) in photoreceptor death. In situ hybridization on retinal cryosections revealed that Cxcl1 and Cxcl10 are expressed by Müller cells and RPE, while Ccl3, Ccl4, and Ccl7 are expressed by microglia - predominately in regions of heavy photoreceptor degeneration. In conjunction, a localized recruitment of IBA-expressing monocytes/microglia (p<0.05) to the degenerating ONL was observed.
Our data indicate that the retina actively contributes to the guidance of the neuroinflammatory response following retinal injury, through local expression of multiple chemokines coordinated by Muller cells, microglia, and RPE. Characterization of the chemokine immune pathways is crucial in clarifying the underling pathogenesis of inflammation in retinal degenerations, such as AMD.
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