Alleviation of experimental arthritis in SKG mice through Nr4a1 agonization

TL;DR

This study shows that activating Nr4a1 with Cytosporone B reduces arthritis in mice by suppressing harmful T cell activity and inflammation.

Contribution

Demonstrates that Nr4a1 agonization with Cytosporone B ameliorates T cell-driven autoimmune arthritis in SKG mice.

Findings

CsnB reduced arthritis severity and Th17 cell populations in SKG mice.

CsnB suppressed T cell activation and inflammatory gene expression in vitro.

CsnB inhibited Th17 differentiation by reducing CD130 expression and IL-6 signaling.

Abstract

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.

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.

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.

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.

Side-by-side infographic compares immune mechanisms in arthritis without treatment versus with Cytosporone B treatment, showing self-reactive T cells leading to Th17 cells and arthritis in untreated, while Cytosporone B blocks Th17 formation and reduces inflammatory signaling, lowering arthritis development in mice.

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