June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Markers of Protective Microglia in Mouse Models of Outer Retinal Degeneration Are Present in Human AMD
Author Affiliations & Notes
  • Chen Yu
    Ophthalmology, Duke University, Durham, North Carolina, United States
  • Eleonora M Lad
    Ophthalmology, Duke University, Durham, North Carolina, United States
  • Alan D Proia
    Pathology, Duke University, Durham, North Carolina, United States
    Ophthalmology, Duke University, Durham, North Carolina, United States
  • Daniel R Saban
    Ophthalmology, Duke University, Durham, North Carolina, United States
    Immunology, Duke University, Durham, North Carolina, United States
  • Footnotes
    Commercial Relationships   Chen Yu, None; Eleonora Lad, Apellis (C), Galimedix (C), Gemini Therapeutics (C), Novartis (F), Retrotope (C), Roche (F), Roche (C); Alan Proia, Novartis (F), Roche (F); Daniel Saban, Aeri (C), Dompe (F), Novartis (F), Roche (C)
  • Footnotes
    Support  NIH Grant R01EY030906, NIH Grant R01EY021798, VA Merit Award I01 CX002116-01, Research to Prevent Blindness, NIH Core Grant P30EY005722
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 2244. doi:
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    • Get Citation

      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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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : 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.

Methods : 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.

Results : 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).

Conclusions : 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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