Activation of glucocorticoid receptors in Müller glia is protective to retinal neurons and suppresses microglial reactivity.
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.
Department of Neuroscience, College of Medicine, Wexner Medical Center, The Ohio State University, 4190 Graves Hall, 333 West 10th Ave., Columbus, OH 43210-1239, USA.
Donika
D
Gallina
Department of Neuroscience, College of Medicine, Wexner Medical Center, The Ohio State University, 4190 Graves Hall, 333 West 10th Ave., Columbus, OH 43210-1239, USA.
Christopher Paul
CP
Zelinka
Havener Eye Institute, Department of Ophthalmology and Visual Science, College of Medicine, The Ohio State University, 915 Olentangy River Road, Suite 5000, Columbus, OH 43212, USA.
Colleen M
CM
Cebulla
Department of Neuroscience, College of Medicine, Wexner Medical Center, The Ohio State University, 4190 Graves Hall, 333 West 10th Ave., Columbus, OH 43210-1239, USA. Electronic address: Andrew.Fischer@osumc.edu.
Andy J
AJ
Fischer
D000818:Animals; D000831:Animals, Newborn; D002452:Cell Count; D002645:Chickens; D003078:Colchicine / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D063928:Ependymoglial Cells / Q000187:drug effects / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D056965:Injections, Intraocular; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000166:cytology*; D012163:Retinal Detachment / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology; D014795:Visual Pathways / Q000187:drug effects / Q000378:metabolism; D029961:Zebrafish Proteins
D016207:Cytokines; D018690:Excitatory Amino Acid Agonists; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D011965:Receptors, Glucocorticoid; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors; D050257:Tubulin Modulators; D029961:Zebrafish Proteins; D016222:Fibroblast Growth Factor 2; D016202:N-Methylaspartate; D003078:Colchicine
Microglia; Müller glia; Neuronal survival; Retina; Retinal detachment