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Chen Yu, Eleonora M Lad, Alan Proia, Daniel R Saban; Augmentation of Protective Microglia Restricts Outer Retinal Degeneration and Preserves Vision. Invest. Ophthalmol. Vis. Sci. 2022;63(7):23.
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Immune processes in many forms of retinal degeneration, including age-related macular degeneration (AMD), involves migration and ectopic accumulation of macrophages in the subretinal space. Recently, we described a unique subtype of bona fide microglia that are dominant in the subretinal space in mouse models of retinal degeneration. These subretinal microglia are transcriptionally reprogrammed and contribute to protecting the retina pigment epithelium (RPE) from damage caused by degeneration. These findings now prompt new investigations aimed at identifying the molecular players underlying this protective response.
We utilized single cell RNA-seq and compared subretinal microglia in four distinct disease mouse models that represent key pathobiological aspects of outer retinal degenerative diseases. These individual models included the light damage model, the sodium iodate induced RPE injury model, rhodopsin-P23H knockin mice, and an advanced aging model of 2-year-old mice. Global and microglial-conditional knockout mice were generated to assess the contributions of microglia in mediating this protective response.
We found that the transcriptional signature of subretinal microglia is consistent among all mouse models studied. Confocal microscopy revealed that subretinal Iba1+ cells dominantly expressed markers of this signature in all mouse models. Likewise, these markers were also observed in human postmortem retinas with intermediate to advanced AMD, whereas few positive cells were found in either healthy or early AMD subjects. Moreover, we showed that genetic inhibition of this protection exacerbated death of photoreceptors, loss of RPE integrity and impairment of visual function in multiple models. Importantly, the protective activity by microglia was compromised during retinal degeneration, whereas pharmacological bolstering of subretinal microglia protected the retina from degeneration and better-preserved the RPE integrity and vision in mice.
Our findings demonstrate a general signature of subretinal microglia in mice and the possible relevance of this microglial population in forms of human AMD. These results provide a novel focal point for therapeutic strategies in vision preservation with retinal degenerative diseases.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.
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