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Itay Chowers, Sarah Hayoun, Batya Rinsky, Shira Hagbi-Levi, Michelle Grunin; The Neurotoxic Phenotype of Macrophages from Patients with Age-Related Macular Degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 2019;60(9):1221. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Recent studies implicated macrophages in age-related macular degeneration (AMD) through both the atrophic (aAMD) and neovascular (nvAMD) stages. Here, we aim to investigate the effect of distinct subtypes of macrophages from AMD patients on photoreceptor cell survival, and their involvement in the progression of aAMD.
Monocytes were isolated from AMD patients and polarized into four subtypes of macrophages: M0 (MCSF), M1 (LPS+IFN), M2a (IL-13, IL-4), and M2c (IL-10). Macrophages were evaluated in an ex vivo model of mouse retinal explant. To that end, macrophages subtypes were co-cultured with the retinal explant for 16 hours followed by assessment of photoreceptor cell death using TUNEL assay. Macrophages were also tested in vivo in a model for photic retina injury in albino mice. Mice were exposed to 8000 lux of white light for 3 hours. Light-injured mice were then injected intravitreally with subtypes of Dio-stained macrophages (adoptive transfer). Electroretinogram (ERG) recording and outer nuclear layer (ONL) thickness per histology were then measured 7 days after the light injury to evaluate visual function and photoreceptor survival in each group, respectively.
Monocytes from AMD patients (n=7, female/male=3/4, mean age=69.6) were evaluated. In the in vivo model of photic retinal injury, ERG results showed a mean reduction of 50% of the b-wave amplitudes in eyes injected with M2a macrophages as compared to control eyes injected with PBS (p=0.02). Adoptive transfer of other macrophage subtypes to the vitreous was not associated with decreased ERG amplitudes in this model. Histological analysis revealed a ONL nuclei loss with a mean reduction of 35% in eyes injected with M2a macrophages as compared to control (p=0.01). In the in vitro model of retinal explant, M2a macrophages were associated with a mean increased photoreceptor cell death of 57 % as compared to control (p=0.003). Enhanced production (2-fold, p<0.05) of reactive oxygen species (ROS) was detected in association with M2a macrophages in cell culture.
M2a macrophage subtype from AMD patients show a neurotoxic effect on photoreceptors in in vitro and in vivo models. The relevance of such an effect for photoreceptor loss during the course of aAMD progression should be further evaluated, as well as the role of macrophages as a potential therapeutic target for aAMD.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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