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Therapeutic Effects of Upadacitinib on Experimental Autoimmune Uveitis: Insights From Single-Cell Analysis

Huang, Z;Jiang, Q;Chen, J;Liu, X;Gu, C;Tao, T;Lv, J;Li, Z;Li, Z;Su, W;

This study aimed to elucidate the impact of upadacitinib, a Janus kinase 1 (JAK1)-specific inhibitor, on experimental autoimmune uveitis (EAU) and explore its underlying mechanisms.We utilized single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) to investigate the JAK/signal transducer and activator of transcription (STAT) pathway in peripheral blood mononuclear cells (PBMCs) of 12 patients with Vogt-Koyanagi-Harada (VKH) disease and cervical draining lymph node (CDLN) cells of EAU. After treating EAU with upadacitinib, we analyzed immune cell gene expression and cell-cell communication by integrating scRNA data. Additionally, we applied flow cytometry and western blot to analyze the CDLN cells.The JAK/STAT pathway was found to be upregulated in patients with VKH disease and EAU. Upadacitinib effectively alleviated EAU symptoms, reduced JAK1 protein expression, and suppressed pathogenic CD4 T cell (CD4TC) proliferation and pathogenicity while promoting Treg proliferation. The inhibition of pathogenic CD4TCs by upadacitinib was observed in both flow cytometry and scRNA data. Additionally, upadacitinib was found to rescue the interferon-stimulated gene 15 (ISG15)+ CD4TCs and CD8 T and B cell ratios and reduce expression of inflammatory-related genes. Upadacitinib demonstrated the ability to inhibit abnormally activated cell-cell communication, particularly the CXCR4-mediated migration pathway, which has been implicated in EAU pathogenesis. CXCR4 inhibitors showed promising therapeutic effects in EAU.Our findings indicate that the JAK1-mediated signaling pathway is significantly upregulated in uveitis, and upadacitinib exhibits therapeutic efficacy against EAU. Furthermore, targeting the CXCR4-mediated migration pathway could be a promising therapeutic strategy.