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 <i>apolipoprotein E</i> (<i>APOE</i>) expression in their peripheral blood mononuclear cells (PBMCs). In addition, single-cell RNA sequencing of retinal microglia also identified an up-regulated expression of <i>APOE</i> 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 <i>APOE</i> 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 <i>APOE</i>, microglia, and EAU, and it is found that <i>APOE</i> is indispensable for EAU induction as <i>APOE</i>^-/- mice failed to develop EAU. In vitro studies using microglial cells further demonstrated that <i>APOE</i> is positively corelated with microglial inflammation, which could be reversed by knocking down <i>APOE</i> using short hairpin RNA. Proteomic analysis indicated that <i>APOE</i>-mediated microglial activation relies on reactive oxygen species (ROS) pathway, through <i>peptidyl prolyl isomerase F</i> (<i>PPIF</i>), which was further verified in PBMCs derived from patients with AU. Supplementation of <i>PPIF</i> reverses <i>APOE</i> deficiency-caused ROS activation in vitro. In addition, Adeno-associated virus-mediated overexpression of <i>PPIF</i> exacerbated EAU phenotype, suggesting its important role in driving uveitis initiation. These results provide an understanding of <i>APOE</i> and <i>PPIF</i> in the pathogenesis of uveitis.