Abstract
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-ĸB is critical for the production and function of most inflammatory cytokines. However, given its essential role in physiologic processes, targeting NF-ĸB is precarious. Hence, identifying pathways downstream of NF-ĸB that selectively govern the expression of inflammatory cytokines in inflammatory arthritis would be advantageous. We have previously identified IĸBζ as a unique inflammatory signature of NF-ĸB that controls the transcription of inflammatory cytokines only under pathologic conditions while sparing physiologic NF-ĸB signals.
Methods:
We generated mice harboring myeloid, lymphoid, and global deletion of Nfkbiz (the gene encoding IĸBζ). These models were subjected to serum transfer-induced arthritis. Additionally, pharmacologic inhibitors of IĸBζ 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 IĸBζ+ 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 IĸBζ-mediated inflammatory factors. Further, in silico screen identified 8-hydroxyquinoline (HQ) as a putative inhibitor of IĸBζ not affecting physiologic NF-ĸB activity. Congruently, systemic administration of either DI or HQ inhibited joint swelling and damage.
Conclusion:
Our study positions IĸBζ as an inflammation-specific target for therapeutic consideration in rheumatoid arthritis because its inhibition spares the beneficial functions of NF-ĸB.