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

Abstract

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() expression in their peripheral blood mononuclear cells (PBMCs). In addition, single-cell RNA sequencing of retinal microglia also identified an up-regulated expression ofin a murine model of experimental AU (EAU). Our results and others previously suggested that microglia are tightly associated with the development of AU. Meanwhile, althoughhas 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, microglia, and EAU, and it is found thatis indispensable for EAU induction asmice failed to develop EAU. In vitro studies using microglial cells further demonstrated thatis positively corelated with microglial inflammation, which could be reversed by knocking downusing short hairpin RNA. Proteomic analysis indicated that-mediated microglial activation relies on reactive oxygen species (ROS) pathway, through(), which was further verified in PBMCs derived from patients with AU. Supplementation ofreversesdeficiency-caused ROS activation in vitro. In addition, Adeno-associated virus-mediated overexpression ofexacerbated EAU phenotype, suggesting its important role in driving uveitis initiation. These results provide an understanding ofandin the pathogenesis of uveitis.