Apolipoprotein E drives microglia activation in the development of autoimmune uveitis through up-regulation of peptidyl prolyl isomerase F.

Autoimmune uveitis (AU) is a category of sight-threatening diseases with different pathological causes. Transcriptomic analysis of patients with AU revealed a highly oxidative stress profile as well as an up-regulated apolipoprotein E (APOE) expression in their peripheral blood mononuclear cells (PBMCs). In addition, single-cell RNA sequencing of retinal microglia also identified an up-regulated expression of APOE in a murine model of experimental AU (EAU). Our results and others previously suggested that microglia are tightly associated with the development of AU. Meanwhile, although APOE has been reported to play a myriad of functions ranging from lipid metabolism to neural regeneration, little is known about its detailed mechanism in the development of AU. In this study, a murine EAU model was used to investigate the association between APOE, microglia, and EAU, and it is found that APOE is indispensable for EAU induction as APOE(-/-) mice failed to develop EAU. In vitro studies using microglial cells further demonstrated that APOE is positively corelated with microglial inflammation, which could be reversed by knocking down APOE using short hairpin RNA. Proteomic analysis indicated that APOE-mediated microglial activation relies on reactive oxygen species (ROS) pathway, through peptidyl prolyl isomerase F (PPIF), which was further verified in PBMCs derived from patients with AU. Supplementation of PPIF reverses APOE deficiency-caused ROS activation in vitro. In addition, Adeno-associated virus-mediated overexpression of PPIF exacerbated EAU phenotype, suggesting its important role in driving uveitis initiation. These results provide an understanding of APOE and PPIF in the pathogenesis of uveitis.