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Bin Lin, Bo Peng; Suppression of microglial activation is neuroprotective in a mouse model of human retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4364.
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© ARVO (1962-2015); The Authors (2016-present)
Retinitis Pigmentosa (RP) is a photoreceptor-degenerative disease caused by various mutations that result in rod photoreceptor cell death followed by gradual death of cone photoreceptors. The molecular mechanisms that lead to the secondary cone death are not yet fully understood. Neuroinflammation contributes to the progression of many chronic neurodegenerative disorders. However, the nature of microglia involvement in RP has not been documented. In this study, we explored the role of microglia as a contributor to photoreceptor degeneration in the rd10 mouse model of RP.
we backcrossed Cx3cr1 knockout mice , in which the Cx3cr1 gene was replaced with a cDNA encoding green fluorescent protein (GFP), into the rd10 background creating a new line of mice. To validate the importance of inflammation in RP, minocycline, an inhibitor of microglial activation, was injected into the peritoneum of rd10 mice. We investigated the effect of microglia activation on photoreceptor survival, using a combination of immunocytochemistry, RT-PCR, western blot analysis, and a series of simple visual tests.
We found that microglia activation and migration into the subretinal space preceded photoreceptor apoptosis in rd10 retinas. Suppression of microglia activation by minocycline resulted in down-regulation of pro-inflammatory cytokines and chemokines and pro-apoptotic molecules, leading to significant structural and functional rescue in rd10 retinas. We also identified that minocycline exerted its neuroprotective effects through both anti-apoptotic and anti-inflammatory mechanisms.
Our data demonstrated that activated microglia contributed to the severity of RP disease and played an important role in regulating the survival of photoreceptors in RP retinas. Therefore, modulating microglia activation could be a potential treatment strategy aimed at improving photoreceptor survival in human RP.
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