The Unexpected Role of Subretinal Microglia in Aging Retina
The Ksander Lab at Boston’s Schepens Eye Research Institute has unveiled valuable insights into the role of subretinal microglia in safeguarding vision during aging. Published in the journal Immunity & Ageing, this research highlights the critical function of these immune cells in maintaining retinal health and offers new hope for combating age-related vision loss. Striatech’s OptoDrum was used within this study and played a significant role in assessing visual function.
PUBLICATION
Immunity & Ageing (Oct 14, 2023) “Microglia preserve visual function in the aging retina by supporting retinal pigment epithelial health“
Karg MM, Moorefield M, Hoffmann E, Philipose H, Krasniqi D, Hoppe C, Shu DY, Shirahama S, Ksander BR, Saint-Geniez M
Retinal Pigment Epithelial Cells Undergo Changes During Aging
At the outer bounds of the retina lies the retinal pigment epithelium (RPE), a critical layer of cells responsible for maintaining photoreceptor health. The RPE forms the blood-retina barrier, clears photoreceptor waste, and supplies essential nutrients. However, aging compromises these functions, leading to the accumulation of lipid droplets and photoreceptor debris, structural alterations, and ultimately, the onset of age-related macular degeneration (AMD) – a leading cause of blindness globally.
Aging and Microglia Migration: Implications for Retinal Health and Degeneration
Microglia, the central nervous system’s primary immune cells, are known for their role in maintaining retinal homeostasis and responding to injury or disease. Traditionally, these cells patrol the inner retinal layers. However, the Ksander Lab’s research reveals a fascinating phenomenon: with age, microglia migrate into the subretinal space, the region between photoreceptors and the RPE. This migration, previously underexplored, raises critical questions about its implications for retinal health. Is the migration of microglia protecting the aging retina, or is it a sign of further deterioration?
Unraveling Microglial Function Through Selective Depletion
To investigate, researchers employed a targeted approach, selectively depleting microglia in mice using a CSF1R inhibitor. This method blocked colony-stimulating factor 1 receptor signaling, essential for microglial survival, allowing scientists to observe the effects of microglial absence on retinal health. The study included mice from three age groups: young adults (3 months), aged (18 months), and very old (34 months). Retinal morphology was analyzed using transmission electron microscopy (TEM) and immunofluorescent imaging, while visual function was assessed through electroretinography (ERG) and optomotor response testing using Striatech’s Optodrum™.
OptoDrum™ tests showed that old mice on a depletion diet (lacking subretinal microglia, orange) had significantly worse contrast sensitivity than age-matched mice on a normal diet (gray).
Reproduced from the original article under the Creative Commons Attribution 4.0 International License
Subretinal Microglia: Supporting RPE Cells in Aging Retinas
The study revealed that aged microglia in the subretinal space adopt an amoeboid morphology, indicative of activation and phagocytic activity. These microglia were found to phagocytize photoreceptor outer segments and lipid droplets, effectively compensating for the declining functionality of RPE cells. TEM and immunofluorescent imaging confirmed that microglia were actively supporting the RPE, mitigating the damage caused by aging.
Microglia & Vision: OptoDrum Quantifies Visual Deterioration without Microglia
In microglia-depleted mice, the aging RPE faced accelerated deterioration, with increased cell diameter and reduced cell numbers, signaling stress and structural breakdown. ERG results highlighted the reliance of RPE health on microglial support, as the c-wave – reflecting RPE cell function – was significantly reduced in microglia-depleted mice. These findings emphasize the critical role of microglia in maintaining retinal integrity during aging.
This impact was also demonstrated by the optomotor response. Karg et al. conducted a comprehensive study on the role of microglia in maintaining vision. The study utilized Striatech’s OptoDrum™ to measure various aspects of visual function, including contrast sensitivity and visual acuity. This non-invasive approach allowed for repeated testing, providing a comprehensive view of changes in visual function over time
Initially, the researchers observed that visual acuity declined with age, as anticipated. Surprisingly, when comparing 34-month-old mice with and without microglia, no significant difference in visual acuity was detected. To delve deeper into this unexpected result, the team performed a more thorough analysis of the optomotor response. This detailed examination revealed that mice with intact microglia exhibited superior contrast sensitivity compared to their microglia-depleted counterparts. Ultimately, these findings provided conclusive evidence that subretinal microglia play a crucial protective role in preserving vision, particularly in aging retinas.
Enhancing Microglial Support Could Combat Age-Related Vision Loss
The findings suggest that enhancing the supportive functions of subretinal microglia could offer promising therapeutic avenues for conditions like Age-related Macular Degeneration (AMD). By stepping in to perform RPE cell functions, microglia play a crucial role in preserving retinal integrity and preventing severe degeneration. This opens the door to potential treatments aimed at bolstering microglial activity to combat age-related vision loss.
Original Source: Emilia Kawecka, Technical University of Munich, Student Assistant at Striatech
Original Paper: Karg, M.M., Moorefield, M., Hoffmann, E. et al. Microglia preserve visual function in the aging retina by supporting retinal pigment epithelial health. Immun Ageing 20, 53 (2023). https://doi.org/10.1186/s12979-023-00358-4
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