Microglia dynamics in retinitis pigmentosa model: formation of fundus whitening and autofluorescence as an indicator of activity of retinal degeneration

Abstract

In patients with retinitis pigmentosa (RP), color fundus photography and fundus autofluorescence (FAF) have been used to estimate the disease progression. To understand the origin and the diagnostic interpretation of the fundus color and FAF, we performed in vivo imaging of fundus color and FAF together with histological analyses of the retinal degeneration process using the RP model mice, rd10. FAF partly represented the accumulation of microglia in the photoreceptor outer segments. Fundus whitening suggested the presence of apoptotic cells, which spatiotemporally preceded increase in FAF. We observed two patterns of FAF localization, arcuate and diffuse, each indicating different pattern of apoptosis, wavy and diffuse, respectively. Diffuse pattern of apoptosis was suppressed in dark-raised rd10 mice, in which outer nuclear layer (ONL) loss was significantly suppressed. The occupancy of FAF correlated with the thinning rate of the ONL. Fractalkine, a microglia chemotactic factor, was detected in apoptotic photoreceptors, suggesting chemokine-induced recruitment of microglia into the ONL, which paralleled with accelerated ONL loss and increased FAF occupancy. Thus, we propose that the degree of photoreceptor apoptosis and the rate of ONL thinning in RP patients might be read from the fundus color and the FAF.

Retinal Degeneration and Microglial Dynamics in Mature Progranulin-Deficient Mice

“…Previous studies have demonstrated that retinal microglia are activated and translocated into the subretinal space during healthy aging and retinal disease processes, including age-related macular degeneration and retinitis pigmentosa [ 22 , 23 , 24 ]. Abnormal activation of microglia and fundus lesions have been observed in multiple mouse models of retinal disease, including NCL [ 25 , 26 , 27 , 28 ]. Some studies have demonstrated that pharmacological modulation or ablation of subretinal microglia leads to attenuated photoreceptor degeneration in mouse models of retinal degeneration [ 29 ].…”

Single cell RNA sequencing confirms retinal microglia activation associated with early onset retinal degeneration

“…These findings provide an insight into the microglial response and function during RD in the Mfrp KI/KI model. We hypothesize that activated subretinal microglia remove potentially damaging cell debris 15 , 48 . We also observed that there was a significant increase in cells expressing genes associated with phagocytosis and apoptosis pathways in Mfrp KI/KI retinal microglia (PARP9, ANXA5, TSPO) (Supplementary Fig.…”

“…Interestingly, these mice also develop early-onset autofluorescent retinal spots which are thought to be the result of subretinal deposits 14 . Studies have demonstrated subretinal immune cell infiltration showing positive staining for macrophage 15 , 16 . Recent reports suggest that activation of resident microglia and monocyte derived macrophages could both contribute to subretinal microglia.…”

Development of a novel knockout model of retinitis pigmentosa using Pde6b-knockout Long–Evans rats

“…This pigment-containing region is important for RP research as the area presents many pathologic changes in the RPE, blood vessels, glia, and neurons during RP pathogenesis. Although pigmentary degeneration is observed in some mouse models for retinal degeneration, such as the rd10 mice ( 16 ), there is no reliable rat model, to our knowledge, that can consistently reproduce bone-spicule pigmentation in the fundus. Moreover, as the rat is more biologically parallel to humans, our rat model has greater translational value than previously published mouse models ( 17 ).…”