Microglia preserve visual function loss in the aging retina by supporting retinal pigment epithelial health

Margarete M Karg; May Moorefield; Emma Hoffmann; Hannah Philipose; Drenushe Krasniqi; Cindy Hoppe; Daisy Y Shu; Shintaro Shirahama; Bruce R Ksander; Magali Saint-Geniez

doi:10.1186/s12979-023-00358-4

Microglia preserve visual function loss in the aging retina by supporting retinal pigment epithelial health

Immun Ageing. 2023 Oct 14;20(1):53. doi: 10.1186/s12979-023-00358-4.

Authors

Margarete M Karg^{1

2}, May Moorefield¹, Emma Hoffmann¹, Hannah Philipose¹, Drenushe Krasniqi¹, Cindy Hoppe^{1

2}, Daisy Y Shu^{1

2}, Shintaro Shirahama^{1

2}, Bruce R Ksander^#^{3

4}, Magali Saint-Geniez^#^{1

2}

Affiliations

¹ Schepens Eye Research Institute of Mass Eye and Ear, 20 Staniford St, Boston, MA, 02114, USA.
² Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
³ Schepens Eye Research Institute of Mass Eye and Ear, 20 Staniford St, Boston, MA, 02114, USA. Bruce_Ksander@meei.harvard.edu.
⁴ Department of Ophthalmology, Harvard Medical School, Boston, MA, USA. Bruce_Ksander@meei.harvard.edu.

^# Contributed equally.

Abstract

Background: Increased age is a risk factor for the development and progression of retinal diseases including age-related macular degeneration (AMD). Understanding the changes that occur in the eye due to aging is important in enhancing our understanding of AMD pathogenesis and the development of novel AMD therapies. Microglia, the resident brain and retinal immune cells are associated with both maintaining homeostasis and protection of neurons and loss of microglia homeostasis could be a significant player in age related neurodegeneration. One important characteristic of retinal aging is the migration of microglia from the inner to outer retina where they reside in the subretinal space (SRS) in contact with the retinal pigment epithelial (RPE) cells. The role of aged subretinal microglia is unknown. Here, we depleted microglia in aged C57/BL6 mice fed for 6 weeks with a chow containing PLX5622, a small molecule inhibitor of colony-stimulating factor-1 receptor (Csf1r) required for microglial survival.

Results: The subretinal P2RY12 + microglia in aged mice displayed a highly amoeboid and activated morphology and were filled with autofluorescence droplets reminiscent of lipofuscin. TEM indicates that subretinal microglia actively phagocytize shed photoreceptor outer segments, one of the main functions of retinal pigmented epithelial cells. PLX5622 treatment depleted up to 90% of the retinal microglia and was associated with significant loss in visual function. Mice on the microglia depletion diet showed reduced contrast sensitivity and significantly lower electroretinogram for the c-wave, a measurement of RPE functionality, compared to age-matched controls. The loss of c-wave coincided with a loss of RPE cells and increased RPE swelling in the absence of microglia.

Conclusions: We conclude that microglia preserve visual function in aged mice and support RPE cell function, by phagocytosing shed photoreceptor outer segments and lipids, therefore compensating for the known age-related decline of RPE phagocytosis.

Keywords: Csf1r inhibitor; Microglia; PLX5622; RPE; Retina; Visual function.

Grants and funding

P30 EY003790/EY/NEI NIH HHS/United States