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Xiao Yang, Lian Zhao, Maria M Campos, Mones S Abu-Asab, Davide Ortolan, Nathan Hotaling, Kapil Bharti, Wai T Wong; Sustained Depletion of Choroidal Macrophages is Associated with Choroidal Vascular Atrophy and RPE Disorganization. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5239.
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© ARVO (1962-2015); The Authors (2016-present)
Age-related macular degeneration (AMD), a leading cause of vision loss, features degenerative and inflammatory changes in choroid-RPE complex. However, interactions between constituent cell types (choroidal endothelial cells, RPE cells, and resident choroidal macrophages) under normal and pathological conditions are unclear. We investigate the constitutive role of resident macrophages in the choroid-RPE complex of healthy adult mouse under sustained macrophage depletion.
Adult 3-month old BALB/c mice were administered PLX5622, a synthetic inhibitor of CSF1R signaling, to induce depletion of choroidal macrophages. Choroidal vasculature was assessed using in vivo OCT imaging and histological techniques. RPE organization and choriocapillaris structure were analyzed in sclerochoroidal flatmounts using immunohistochemistry and intravascular DiI perfusion. Molecular changes in the choroid-RPE complex were assessed with RT-PCR. Retinal function was assessed using electroretinography (ERG).
Rapid and prominent depletion of choroidal macrophages (~90%) was achieved after 1 week of PLX5622 administration and was sustained for up to 7 weeks with continued administration. With depletion, choroidal thickness decreased progressively with time to 70% of baseline thickness by 7 weeks, with the choriocapillaris showed corresponding vascular attenuation. While the RPE monolayer remained intact, RPE cell disorganization and loss were evident as decreased cell density, increased mean cell area, increased prevalence of multinucleated cells (>3 nuclei/cell) on quantitative histological analysis, and the loss of apical microvilli on electron microscopy analysis. mRNA levels of RPE-specific genes (RPE65, MITF, RLBP1) were downregulated, as were levels of pro-angiogenic factors (VEGFa, VEGFc), while that of PEDF, an anti-angiogenic factor was increased. ERG responses following depletion showed significantly decreased dark-adapted a- and b-wave amplitudes.
The constitutive presence of resident macrophages in the normal adult choroid appears necessary for the maintenance of healthy choroidal vasculature and RPE organization. Disruptions in interactions between choroidal macrophages and endothelial/RPE cells may contribute to pathologies featuring choroidal atrophy and RPE disorganization, such as those observed in AMD.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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