A peripheral subpopulation of retinal pigment epithelium resists oxidative damage through SERPINE3-mediated Caspase-1 inhibition

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Abstract

Heterogeneous degeneration of the retinal pigment epithelium (RPE) leads to irreversible blindness in diseases associated with macular atrophy. However, the underlying mechanisms of regional RPE degeneration remain poorly understood. To address this gap, this study identifies a peripheral RPE subpopulation through spatial, transcriptomic, and functional analyses, thereby contributing to the understanding of the heterogeneity of degenerative RPE cells. Specifically, omics analyses in human and macaque RPE reveal a peripheral RPE cell population with high SERPINE3 expression, while SERPINE3-GFP knock-in mice show comparable expression patterns. In addition, SMART-seq2 analysis further distinguishes transcriptomic profiles between GFP-positive and GFP-negative RPE cells. Under oxidative stress, SERPINE3 expression increases, and GFP-positive cells exhibit improved survival and reentry into the cell cycle. Notably, genetic studies indicate that SERPINE3 is essential for the oxidative stress resistance of GFP-positive cells. Moreover, loss of SERPINE3 results in regional RPE degeneration and increased microglial accumulation in aged mice. Mechanistically, proteinase screening and co-immunoprecipitation indicate that SERPINE3 targets Caspase-1. Importantly, delivery of SERPINE3 via AAV-Serpine3 partially reduces RPE degeneration in an oxidative damage model. These findings advance the understanding of RPE heterogeneous degeneration and highlight SERPINE3 as a protective factor with therapeutic potential for macular atrophy.

Authors

Huirong Li, Takerra Johnson-Stephenson, Vincent P. Kunze, Wei Yan, David M. McGaughey, Temesgen D. Fufa, Koray Dogan Kaya, Ashley M. Rasys, Davide Ortolan, Dominik Reichert, Congxiao Zhang, Ruchi Sharma, Lijin Dong, Bin Guan, Brian P. Brooks, Tiansen Li, Wei Li, Wencan Wu, Kapil Bharti, Robert B. Hufnagel