Activation of glucocorticoid receptors in Müller glia is protective to retinal neurons and suppresses microglial reactivity

Abstract

Reactive microglia and macrophages are prevalent in damaged retinas. Glucocorticoid signaling is known to suppress inflammation and the reactivity of microglia and macrophages. In the vertebrate retina, the glucocorticoid receptor (GCR) is known to be activated and localized to the nuclei of Müller glia (Gallina et al., 2014). Accordingly, we investigated how signaling through GCR influences the survival of neurons using the chick retina in vivo as a model system. We applied intraocular injections of GCR agonist or antagonist, assessed microglial reactivity, and the survival of retinal neurons following different damage paradigms. Microglial reactivity was increased in retinas from eyes that were injected with vehicle, and this reactivity was decreased by GCR-agonist dexamethasone (Dex) and increased by GCR-antagonist RU486. We found that activation of GCR suppresses the reactivity of microglia and inhibited the loss of retinal neurons resulting from excitotoxicity. We provide evidence that the protection-promoting effects of Dex were maintained when the microglia were selectively ablated. Similarly, intraocular injections of Dex protected ganglion cells from colchicine-treatment and protected photoreceptors from damage caused by retinal detachment. We conclude that activation of GCR promotes the survival of ganglion cells in colchicine-damaged retinas, promotes the survival of amacrine and bipolar cells in excitotoxin-damaged retinas, and promotes the survival of photoreceptors in detached retinas. We propose that suppression of microglial reactivity is secondary to activation of GCR in Müller glia, and this mode of signaling is an effective means to lessen the damage and vision loss resulting from different types of retinal damage.

Immunomodulation-accelerated neuronal regeneration following selective rod photoreceptor cell ablation in the zebrafish retina

“…Further, their data suggest that inhibition of microglia activation is an indirect effect of activated glucocorticoid signaling in MG, the primary site of glucocorticoid receptor expression in chick and several other vertebrate species investigated (49). In contrast to our findings, Dex functioned as a neuroprotectant in the injured chick retina.…”

“…Here, we report chemically enhanced rod photoreceptor regeneration kinetics in zebrafish. Somewhat confoundingly, the glucocorticoid antagonist RU486 has been shown to promote the regeneration of amacrine cells in the chick retina (49). However, this promotion appears to be an effect of MG-derived progenitors on differentiation, because amacrine cells are restored at the expense of MG. We currently are exploring the cellular and molecular mechanisms underlying Dexenhanced regeneration in the fish retina.…”

“…However, a role for inflammation in regulating regeneration following selective neuronal cell ablation has yet to be investigated. Activation of glucocorticoid signaling has been shown to reduce microglial reactivity in the mammalian brain (47,48) and chick retina (49). Therefore, using the intravital imaging techniques detailed above, we first investigated whether exposing larvae to Dex before Mtz-induced rod cell ablation would result in a reduction in microglia migration.…”

“…For instance, liposomeencapsulated clodronate was developed to ablate phagocytic cells and can be used to ablate macrophages and microglia (79). This strategy was used recently to demonstrate that macrophages are necessary for tissue/appendage regeneration (8-10), hair cell replacement (66), and retinal neuroprotection (49,80). Similarly, we used the NTR system to coablate microglia/macrophage and rod cells and then quantified effects on MG/progenitor cell proliferation rates and rod cell regeneration kinetics.…”

The chick eye in vision research: An excellent model for the study of ocular disease

“…Similar to the zebrafish, a network of cell-signaling pathways that influence MGPC-formation is being uncovered in the chick model system. The network of pathways that control the formation of MGPCs is known to include Notch-, Wnt-, MAPK-, Jak/Stat-, mTor-, Hedgehog-, and glucocorticoid-signaling (Fischer et al, 2009a, 2009b, Gallina et al, 2015, 2014; Ghai et al, 2010; Hayes et al, 2007; Todd et al, 2016; Todd and Fischer, 2015; Zelinka et al, 2016). In the mammalian retina, Müller glia retain a severely limited capacity to become MGPCs and this process requires damage followed by growth factor stimulation, or transgenic overexpression of the proneural transcription factor ascl1 (Karl et al, 2008; Ooto et al, 2004; Ueki et al, 2015).…”