Aging, a common risk factor for multiple retinal degeneration diseases, is susceptible to the tissue immune state. Our previous study suggested that a gamma-flicker light (γFL) improves retinal aging features. However, it remains unclear whether γFL could affect the retinal immune function under aging. In this study, we first explored the effects of γFL on astrocyte and microglia morphologies in different inner-retinal layers for mice of 8 w, 9 m, and 18 m. Unfortunately, these morphologies appeared to change only with age independent of 6-d γFL treatment. The immune transcriptomic analysis was then carried out for the whole retina tissue of 20-m mice, and we found that the major histocompatibility complex II (MHC-II) mediated antigen processing and presentation was most affected by γFL. The MHC-II related markers in the retina were then assessed, and the staining of all-age retina flat-mount showed that MHC-II+ cells were ionized calcium-binding adaptor molecule 1 (IBA-1) positive, the cells distributed along the retinal veins. The para-venous MHC-II+ microglia cells were increased with aging and further increased with γFL treatment in 18-m mice. Meanwhile, we found that γFL significantly activated subretinal microglia, whose MHC-II+ subpopulation was significantly increased. Echoing these results, γFL significantly elevated neural-retinal CD74 expression level in the western blotting. Furthermore, amyloid β (Aβ) oligomer solution was injected into the vitreous of 8-w and 9-m mice to mimic retina aging. Expression levels of CD68 and CD74 were increased in these mice after Aβ injection and further increased following 3-d γFL treatment. Similarly, we found that the Aβ-γFL treatment resulted in a linear distribution of MHC-II+ microglia along the retinal veins and brought about a co-staining of Aβ with other activated microglia distant from the veins. Overall, γFL treatment inspires the function of retinal microglia in MHC-II-mediated antigen phagocytosis and presentation under aging, thus being a potential immunomodulatory tool for the treatment of retinal aging or aging-related diseases.

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