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Updated: Mar 14, 2026
An Adoptive Transfer Model of Rheumatoid Arthritis in Mice
Published on: June 6, 2025
Alleviation of experimental arthritis in SKG mice through Nr4a1 agonization
Yoichi Nakayama1, Ryosuke Hiwa1, Ayaka Okubo1
1Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Introduction:
Rheumatoid arthritis (RA), a chronic autoimmune disease, is characterized by CD4+ T cell-mediated synovial inflammation, with T helper (Th)17 cells being implicated in RA pathogenesis. Nr4a1 is an orphan nuclear receptor functioning as a negative regulator of T cell activation and central tolerance. Cytosporone B (CsnB) is a small-molecule agonist of Nr4a1 and can exert immunomodulatory effects. However, its efficacy in T cell-driven autoimmune arthritis remains unclear. This study aimed to investigate the therapeutic effect of CsnB-mediated Nr4a1 agonization on RA development in SKG mice and evaluate its impact on T cell function.
Methods:
The SKG mouse model of T cell-dependent chronic arthritis was constructed via zymosan A induction. The mice were intraperitoneally treated with CsnB, and disease severity and immune cell populations were evaluated by clinical scoring and flow cytometry. In vitro assays were performed to examine T cell antigen receptor (TCR)-induced T cell activation and Th17 differentiation. Additionally, RNA sequencing was performed to profile transcriptomic changes in CD4+ T cells following TCR stimulation.
Results:
CsnB markedly attenuated arthritis development and reduced the population of effector memory and Th17 cells in the spleen and synovium. Furthermore, in vitro assay results showed that CsnB suppressed T cell activation, downregulated interleukin (IL)-2 and activation markers, and repressed inflammatory gene expression. CsnB inhibited Th17 differentiation and IL-6-signal transducer and activator of transcription 3 signaling by reducing CD130 (Il6st) expression.
Discussion:
Altogether, the findings of this study showed that CsnB, one of the agonists of Nr4a1, suppressed TCR-driven T cell activation and Th17 differentiation, thereby ameliorating autoimmune arthritis in SKG mice. These findings highlight the potential of Nr4a1 as an immunotherapeutic target in T cell-mediated autoimmune arthritis, particularly in RA subsets characterized by TCR signaling dysfunction.
