{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T23:11:03Z","timestamp":1791846663465,"version":"4.3.4"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T00:00:00Z","timestamp":1771977600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Rheumatoid arthritis (RA), a chronic autoimmune disease, is characterized by CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell-mediated synovial inflammation, with T helper (Th)17 cells being implicated in RA pathogenesis.\n                      <jats:italic>Nr4a1<\/jats:italic>\n                      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\n                      <jats:italic>Nr4a1<\/jats:italic>\n                      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\n                      <jats:italic>Nr4a1<\/jats:italic>\n                      agonization on RA development in SKG mice and evaluate its impact on T cell function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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.\n                      <jats:italic>In vitro<\/jats:italic>\n                      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\n                      <jats:sup>+<\/jats:sup>\n                      T cells following TCR stimulation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CsnB markedly attenuated arthritis development and reduced the population of effector memory and Th17 cells in the spleen and synovium. Furthermore,\n                      <jats:italic>in vitro<\/jats:italic>\n                      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\u2013signal transducer and activator of transcription 3 signaling by reducing CD130 (\n                      <jats:italic>Il6st<\/jats:italic>\n                      ) expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      Altogether, the findings of this study showed that CsnB, one of the agonists of\n                      <jats:italic>Nr4a1<\/jats:italic>\n                      , suppressed TCR-driven T cell activation and Th17 differentiation, thereby ameliorating autoimmune arthritis in SKG mice. These findings highlight the potential of\n                      <jats:italic>Nr4a1<\/jats:italic>\n                      as an immunotherapeutic target in T cell-mediated autoimmune arthritis, particularly in RA subsets characterized by TCR signaling dysfunction.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1758616","type":"journal-article","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T07:03:39Z","timestamp":1772003019000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Alleviation of experimental arthritis in SKG mice through Nr4a1 agonization"],"prefix":"10.3389","volume":"17","author":[{"given":"Yoichi","family":"Nakayama","sequence":"first","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine","place":["Kyoto, 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