{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:29:18Z","timestamp":1792132158879,"version":"4.4.0"},"reference-count":60,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,10,27]],"date-time":"2024-10-27T00:00:00Z","timestamp":1729987200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Current therapies targeting individual factors in inflammatory arthritis show variable efficacy, often requiring treatment with combinations of drugs, and are associated with undesirable side effects. NF\u2010\u0138B is critical for the production and function of most inflammatory cytokines. However, given its essential role in physiologic processes, targeting NF\u2010\u0138B is precarious. Hence, identifying pathways downstream of NF\u2010\u0138B that selectively govern the expression of inflammatory cytokines in inflammatory arthritis would be advantageous. We have previously identified I\u0138B\u03b6 as a unique inflammatory signature of NF\u2010\u0138B that controls the transcription of inflammatory cytokines only under pathologic conditions while sparing physiologic NF\u2010\u0138B signals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We generated mice harboring myeloid, lymphoid, and global deletion of <jats:italic>Nfkbiz<\/jats:italic> (the gene encoding I\u0138B\u03b6). These models were subjected to serum transfer\u2010induced arthritis. Additionally, pharmacologic inhibitors of I\u0138B\u03b6 were injected intraperitonially. Joint swelling, microcomputed tomography, immunohistochemistry, flow cytometry, and cytokine measurements were conducted using synovial tissue samples.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Global deletion of <jats:italic>Nfkbiz<\/jats:italic> or depletion of neutrophils (vastly I\u0138B\u03b6<jats:sup>+<\/jats:sup> cells) reduced inflammatory synovial cells and increased anti\u2010inflammatory and regenerative synovial cells, plummeted expression of inflammatory factors and ameliorated experimental mouse inflammatory arthritis. Further, expression of immune responsive gene\u20101, the enzyme responsible for itaconate production, was increased in synovial cells. Accordingly, the itaconate derivative dimethyl itaconate (DI) inhibited I\u0138B\u03b6\u2010mediated inflammatory factors. Further, in silico screen identified 8\u2010hydroxyquinoline (HQ) as a putative inhibitor of I\u0138B\u03b6 not affecting physiologic NF\u2010\u0138B activity. Congruently, systemic administration of either DI or HQ inhibited joint swelling and damage.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study positions I\u0138B\u03b6 as an inflammation\u2010specific target for therapeutic consideration in rheumatoid arthritis because its inhibition spares the beneficial functions of NF\u2010\u0138B.<\/jats:p><jats:p><jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art42990-toc-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42990","type":"journal-article","created":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T00:50:35Z","timestamp":1726447835000},"page":"124-139","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["<scp>I\u0138B\u03b6<\/scp> as a Central Modulator of Inflammatory Arthritis Pathogenesis"],"prefix":"10.1002","volume":"77","author":[{"given":"Gaurav","family":"Swarnkar","sequence":"first","affiliation":[{"name":"Washington University School of Medicine  St. Louis Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Musarrat","family":"Naaz","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine  St. Louis Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorothy","family":"Mims","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine  St. Louis Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prashant","family":"Gupta","sequence":"additional","affiliation":[{"name":"Washington University in St. Louis  Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Peterson","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine, HealthSpan Technologies, Inc., and Bioio, Inc.  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