IĸBζ as a Central Modulator of Inflammatory Arthritis Pathogenesis

ObjectiveCurrent 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-& kgreen;B is critical for the production and function of most inflammatory cytokines. However, given its essential role in physiologic processes, targeting NF-& kgreen;B is precarious. Hence, identifying pathways downstream of NF-& kgreen;B that selectively govern the expression of inflammatory cytokines in inflammatory arthritis would be advantageous. We have previously identified I & kgreen;B zeta as a unique inflammatory signature of NF-& kgreen;B that controls the transcription of inflammatory cytokines only under pathologic conditions while sparing physiologic NF-& kgreen;B signals.MethodsWe generated mice harboring myeloid, lymphoid, and global deletion of Nfkbiz (the gene encoding I & kgreen;B zeta). These models were subjected to serum transfer-induced arthritis. Additionally, pharmacologic inhibitors of I & kgreen;B zeta were injected intraperitonially. Joint swelling, microcomputed tomography, immunohistochemistry, flow cytometry, and cytokine measurements were conducted using synovial tissue samples.ResultsGlobal deletion of Nfkbiz or depletion of neutrophils (vastly I & kgreen;B zeta+ 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 I & kgreen;B zeta-mediated inflammatory factors. Further, in silico screen identified 8-hydroxyquinoline (HQ) as a putative inhibitor of I & kgreen;B zeta not affecting physiologic NF-& kgreen;B activity. Congruently, systemic administration of either DI or HQ inhibited joint swelling and damage.ConclusionOur study positions I & kgreen;B zeta as an inflammation-specific target for therapeutic consideration in rheumatoid arthritis because its inhibition spares the beneficial functions of NF-& kgreen;B. imageConclusionOur study positions I & kgreen;B zeta as an inflammation-specific target for therapeutic consideration in rheumatoid arthritis because its inhibition spares the beneficial functions of NF-& kgreen;B. image