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Enrique J de la Rosa, Catalina Hernández-Sánchez, Alberto M Hernández-Pinto, María Platón, Miguel Marchena, Noemí Álvarez-Lindo, Ana I Arroba, Sean Jmaeff, Pablo F Barcelona, H Uri Saragovi; Targeted modulation of the glial inflammatory response in Retinitis Pigmentosa attenuates photoreceptor cell death.. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6197.
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© ARVO (1962-2015); The Authors (2016-present)
Retinitis Pigmentosa (RP) is a heterogeneous group of genetic retinal dystrophies. In most forms of RP, photoreceptor cell death is associated with disease progression. Reactive Müller cell gliosis and microglial activation are also found, often prior to photoreceptor death. Here, we studied inflammatory pathways, arising from Müller cell and microglia, that regulate neuronal cell death.
We analyzed the expression of pro-inflammatory cytokines and of markers of reactive Müller cell gliosis and microglial activation by qRT-PCR and immunohistochemistry in retinas from wild type and RP mouse models. Growth factors and pharmacological agents were tested in retinal explants ex vivo and by intravitreal injection in vivo. The agents were selected to modulate the glial inflammatory response. The treatments included clodronate-liposomes (to cause depletion of microglia), IGF-I (to polarize microglia response), and antagonists of the P75(NTR) receptor (a receptor present in Müller and glial cells and whose activity stimulates TNFα production).
A marked increase in GFAP and TNFα transcription preceded photoreceptor cell death in RP retinas. Reduced photoreceptor cell death, better preservation of the outer nuclear layer, and decreased gliosis were observed upon treatment.
Our results suggest the possible existence in the RP retinas of a pro-inflammatory loop mediated by the activation of P75(NTR) in Müller glial cells, which causes production of TNFα. Modulation of the P75(NTR) inflammatory response is a possible target to attenuate RP progression.
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