Lipid metabolism analysis reveals that DGAT1 regulates Th17 survival by controlling lipid peroxidation in uveitis

Lipid metabolism is closely linked with antitumor immunity and autoimmune disorders. However, the precise role of lipid metabolism in uveitis pathogenesis is not clear. In our study, we analyzed the single-cell RNA-Seq (scRNA-Seq) data from cervical draining lymph nodes (CDLNs) of mice with experimental autoimmune uveitis (EAU), revealing an increased abundance of fatty acids in Th17 cells. Subsequent scRNA-Seq analysis identified the upregulation of DGAT1 expression in EAU and its marked reduction under various immunosuppressive agents. Suppression of DGAT1 prevented the conversion of fatty acids into neutral lipid droplets, resulting in the accumulation of lipid peroxidation and subsequent reduction in the proportion of Th17 cells. Inhibiting lipid peroxidation by Ferrostatin-1 effectively restored Th17 cell numbers that were decreased by DGAT1 inhibitor. Moreover, we validated the upregulation of DGAT1 in CD4+ T cells from patients with Vogt-Koyanagi-Harada (VKH) disease, a human uveitis. Inhibiting DGAT1 induced lipid peroxidation in human CD4+ T cells and reduced the proportion of Th17 cells. Collectively, our study focused on elucidating the regulatory mechanisms underlying Th17 cell survival and proposed that targeting DGAT1 may hold promise as a therapeutic approach for uveitis.