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.
Highlights
In patients with retinitis pigmentosa (RP), color fundus photography and fundus autofluorescence (FAF) have been used to estimate the disease progression
The total outer nuclear layer (ONL) loss during the time course (P16–P60) was in the order as: central retina raised under regular light cycle > peripheral retina raised under regular light cycle > peripheral retina raised in dark > central retina raised in dark, which seemed to correlate with the sum of the FAF area during the time course (Supplemental Fig. 3B). These results suggest that regarding the correlation between the FAF area and the type of photoreceptor apoptosis, the peripheral arcuate FAF may follow the initial event of early photoreceptor apoptosis which occurs regardless of the light condition, while widespread diffuse patterns of apoptosis and increased FAF are suppressed in dark environment, leading to ONL protection
The retinal pigment epithelium (RPE) cells in the central but not the peripheral retina of rd[10] were active like microglia, changing their morphologies and accumulating autofluorescent granules in their cell bodies. These results suggest that RPE cells together with microglia contribute to the formation of FAF in RP patients
Summary
In patients with retinitis pigmentosa (RP), color fundus photography and fundus autofluorescence (FAF) have been used to estimate the disease progression. It is reported that chemokines such as fractalkine/CX3CL111 and MCP-1/ CCL212 are expressed in apoptotic photoreceptors and recruit microglia to the degenerating ONL in a light damaged retinal degeneration model It is unknown whether these chemokines play a part to attract microglia in the retinas of RP patients. In order to verify the hypothesis, we performed three experiments using rd[10] mice: (1) in vivo FAF imaging during the retinal degeneration, (2) histopathological examination of retinal specimen at the same time points with in vivo FAF imaging to investigate the related pathological event such as apoptosis of the photoreceptors and infiltration of microglia, and (3) analyses of the expression levels and the localization of microglial chemotactic factors, fractalkine and MCP-1. Since it is known that protection from light is effective in rd[10] mice to delay the progress of the d isease[13], we bred rd[10] mice in dark to examine the parameters change in vivo, which are presumably involved in the delay of the disease
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