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Chen Yu, Eleonora M Lad, Alan D Proia, Daniel R Saban; Markers of Protective Microglia in Mouse Models of Outer Retinal Degeneration Are Present in Human AMD. Invest. Ophthalmol. Vis. Sci. 2021;62(8):2244.
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Many, if not most, forms of retinal degeneration, including age-related macular degeneration (AMD), involve the ectopic accumulation of subretinal macrophages, but their role in human diseases remains elusive. We recently described a unique subtype of bona fide microglia that are dominant in the subretinal space in the light damage (LD) paradigm and rhodopsin P23H mutant knockin mice. These subretinal microglia are transcriptionally reprogrammed and contribute to restricting disease progression, such as loss of structural integrity of the retinal pigment epithelium (RPE) and death of photoreceptors. However, whether this population of reprogrammed microglia is a general response across etiologically distinct forms of degeneration, including human AMD, is unknown.
To address this question, we utilized single cell RNA-sequencing, and compared our findings in LD model (O’Koren and Yu et al, 2019) with another three distinct disease models in mice. These include: an acute model in NaIO3 mediated RPE injury; a chronic degeneration model of P23H mice; and advanced aging model of wildtype 2-year-old mice. Furthermore, selected markers were analyzed by immunolabeling and confocal microscopy in mouse models and also examined in human post-mortem macular sections from a total of 36 patients categorized by Sarks’ grading system.
We showed that transcriptional reprogrammed microglia are conserved among all mouse models studied. Moreover, confocal microscopy revealed that subretinal Iba1+ cells dominantly expressed markers of this reprogramming in all four mouse models. Likewise, in human postmortem retina we observed enriched subretinal staining of such markers in subjects with intermediate to advanced AMD (Sarks 3, 4, and 5), whereas few positive cells were found in control or early AMD subjects (Sarks 1 and 2).
Our findings demonstrate that transcriptionally programed microglia in the subretinal space are present in the studied acute and progressive models of degeneration, as well as in advanced aging mice. Importantly, we show evidence that this unique population may also be relevant in forms of human AMD.
This is a 2021 ARVO Annual Meeting abstract.
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