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Chris Zelinka, Melissa Scott, Andrew Fischer; Reactive microglia and the formation of Müller glia-derived retinal progenitors. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5583. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Reactive microglia are prevalent in retinas where Müller glia have been stimulated to become proliferating progenitor-like cells. Thus, the purpose of this study was to investigate whether the activation or ablation of microglia influences the formation of Müller glia-derived progenitors in the chick retina in vivo. Further, we examine whether the activation or ablation of microglia influences the survival of neurons in damaged retinas.
Interleukin- 6 (IL6) and/or Fibroblast growth factor 2 (FGF2) were injected into the vitreous chamber of postnatal chicks. NMDA was used to elicit excitotoxic retinal damage. The combination of IL6 and clodronate-liposomes was used to ablate microglia. Immunocytochemistry was used to identify different types of reactive and proliferating glia. TUNEL was used to identify dying cells.
IL6 stimulated the reactivity of microglia, which included the up-regulation of CD45 and lysosomal membrane glycoprotein, and acquisition of ameboid morphology. Activation of microglia with IL6 transiently protects retinal neurons from NMDA-induced damage and this effect was obviated when the microglia were ablated. The application of IL6 after NMDA-treatment caused widespread retinal folds and detachments, and these IL6-induced folds/detachments were completely prevented by the ablation of microglia. When the microglia were ablated, the formation of Müller glia-derived progenitors was greatly diminished in damaged retinas or in response to stimulation with the combination of insulin and FGF2. The combination of IL6 and FGF2 stimulated the formation of proliferating Müller glia-derived progenitors in the absence of retinal damage. The activation of microglia and ablation of microglia correlated with increases and decreases, respectively, in retinal levels of pro-inflammatory cytokines and Notch-signaling.
We conclude that reactive microglia profoundly influence the ability of Müller glia to become proliferating progenitor-like cells. We propose that activation of microglia with IL6, and accompanying increases in pro-inflammatory cytokines and Notch-signaling, enhances the ability of Müller glia to become progenitors.
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