Oleic acid regulates CD4+ T cells differentiation by targeting ODC1-mediated STAT5A phosphorylation in Vogt-Koyanagi-Harada disease.

Background: Vogt-Koyanagi-Harada (VKH) is a multisystemic autoimmune disorder characterized by bilateral panuveitis frequently accompanied by neurologic manifestations. While metabolic dysregulation is increasingly recognized in the context of autoimmune diseases, the role of specific metabolites in VKH disease remains unexplored.

Methods: Non-targeted and targeted metabolomics analysis, phospho-antibody array, proteome microarray, surface plasmon resonance, and molecular simulation were used to identify molecular target of OA.

Results: We investigated metabolic profile of VKH disease and found that oleic acid (OA) was enriched in this disease. A series of functional assays showed that OA could exacerbate experimental autoimmune uveitis (EAU) in association with increased frequency of Th1 and Th17 cells and decreased proportion of Treg cells in vitro. However, the specific molecular target of OA remains elusive. Through proteome microarrays, molecular simulations and surface plasmon resonance assays, Ornithine decarboxylase 1 (ODC1) was identified as target protein of OA. OA could bind to ODC1, increase ODC1 protein expression in both a time- and concentration-dependent manner and promote subsequently putrescine production. Phospho-antibody array analysis revealed that OA inhibited phosphorylation of STAT5A (Y694) in CD4+T cells, leading to imbalance of Th1/Th17 and Treg cells and decreased transcription of IL-10. OA upregulated ODC1 protein and putrescine levels through binding to LYS-78, inhibited phosphorylation of STAT5A protein and subsequently decreased binding of STAT5A at IL-10 promoter.

Conclusion: These results reveals that OA could be a crucial metabolite for modulation of CD4+T cell differentiation and that ODC1-mediated phosphorylation and transcriptional activity of STAT5A contributes to development of VKH disease progression, highlighting ODC1 as a novel therapeutic target in VKH disease.