| First Author | Swarnkar G | Year | 2025 |
| Journal | Arthritis Rheumatol | Volume | 77 |
| Issue | 2 | Pages | 124-139 |
| PubMed ID | 39279148 | Mgi Jnum | J:360492 |
| Mgi Id | MGI:7797651 | Doi | 10.1002/art.42990 |
| Citation | Swarnkar G, et al. (2024) IkBzeta as a Central Modulator of Inflammatory Arthritis Pathogenesis. Arthritis Rheumatol |
| abstractText | OBJECTIVE: 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-kB is critical for the production and function of most inflammatory cytokines. However, given its essential role in physiologic processes, targeting NF-kB is precarious. Hence, identifying pathways downstream of NF-kB that selectively govern the expression of inflammatory cytokines in inflammatory arthritis would be advantageous. We have previously identified IkBzeta as a unique inflammatory signature of NF-kB that controls the transcription of inflammatory cytokines only under pathologic conditions while sparing physiologic NF-kB signals. METHODS: We generated mice harboring myeloid, lymphoid, and global deletion of Nfkbiz (the gene encoding IkBzeta). These models were subjected to serum transfer-induced arthritis. Additionally, pharmacologic inhibitors of IkBzeta were injected intraperitonially. Joint swelling, microcomputed tomography, immunohistochemistry, flow cytometry, and cytokine measurements were conducted using synovial tissue samples. RESULTS: Global deletion of Nfkbiz or depletion of neutrophils (vastly IkBzeta(+) cells) reduced inflammatory synovial cells and increased anti-inflammatory and regenerative synovial cells, plummeted expression of inflammatory factors and ameliorated experimental mouse inflammatory arthritis. Further, expression of immune responsive gene-1, the enzyme responsible for itaconate production, was increased in synovial cells. Accordingly, the itaconate derivative dimethyl itaconate (DI) inhibited IkBzeta-mediated inflammatory factors. Further, in silico screen identified 8-hydroxyquinoline (HQ) as a putative inhibitor of IkBzeta not affecting physiologic NF-kB activity. Congruently, systemic administration of either DI or HQ inhibited joint swelling and damage. CONCLUSION: Our study positions IkBzeta as an inflammation-specific target for therapeutic consideration in rheumatoid arthritis because its inhibition spares the beneficial functions of NF-kB. |
