Single-cell RNA sequencing reveals beneficial mechanisms of Exendin-4 in autoimmune uveitis

Autoimmune uveitis (AU), a sight-threatening inflammatory eye disease, is a leading cause of irreversible vision loss. Current treatments are limited by suboptimal efficacy and significant complications, highlighting the need for new therapeutic strategies. Exendin-4 (Ex-4), a glucagon-like peptide-1 receptor agonist primarily used for glycemic control and weight management, has recently shown potential anti-inflammatory effects. However, its role in AU remains unexplored. Here, we demonstrated that Ex-4 treatment effectively alleviated EAU symptoms. Our analysis revealed that Ex-4 partially reversed both the proportional changes and transcriptional alterations in immune cell populations during EAU. Bioinformatic analysis showed that Ex-4 suppressed the EAU-induced upregulation of Pim1 expression. Subsequent experiments revealed that Ex-4 restored the effector T (Teff) /regulatory T (Treg) cell balance via the suppression of the PIM1-protein kinase B (AKT)-Forkhead box O1 (FOXO1) pathway.These effects were further observed in patients with Vogt-Koyanagi-Harada disease (VKH), a human uveitis. Our study provides valuable insights into Ex-4- mediated immune modulation and highlights potential therapeutic targets for autoimmune uveitis.