Photoreceptor cell death directly causes blindness in retinal degeneration (RD) including age-related macular degeneration and retinitis pigmentosa. Photoreceptor cells cannot be repaired once they are damaged, as they are a part of the central nervous system. Hence, considering how to prevent photoreceptor cell damage is important in the treatment of RD. Accumulating evidence suggests that microglia, resident macrophages in the retina, and bone marrow-derived macrophages can cause retinal inflammation, which accelerates photoreceptor cell death. However, details of when and how these cells are activated during RD remain uncertain. Therefore, it is important to clarify which cells play a dominant role in fueling retinal inflammation. To date, distinguishing microglia from macrophages is technically difficult using conventional methods such as those involving cell markers. Recently, we developed Mertk^-/-Cx3cr1^GFP/+Ccr2^RFP/+ mice, spontaneous onset animal model, which enabled microglia to be distinguished from bone marrow-derived macrophages without special techniques. Mertk^-/-Cx3cr1^GFP/+Ccr2^RFP/+ mice showed Cx3cr1-positive microglia migration from the inner retina to the subretinal space, followed by the Ccr2-positive macrophage infiltration into the subretinal space. In the subretinal space, activated microglia, which phagocytized the outer segment of the photoreceptor cells and showed amoeboid shape, became Cx3cr1- and Ccr2-dual-positive, indicating Ccr2 expression in the Cx3cr1-positive microglia is a feature of microglial activation in RD. On the contrary, Mertk^+/+Cx3cr1^GFP/+Ccr2^RFP/+ mice, which did not develop RD, showed only ramified shaped Cx3cr1-positive microglia in the inner retina, and there is no Ccr2-positive macrophage. Mertk^-/-Cx3cr1^GFP/+Ccr2^RFP/+ mice, spontaneous RD onset model, enable the observation of microglial activation associated with photoreceptor cell death over time during the course of RD and may be useful for developing inflammation-targeted treatment strategies for RD in the future.
Nippon Ganka Gakkai Zasshi (J Jpn Ophthalmol Soc) 121: 815-828, 2017.