{"doi":"10.1002/art.42990","title":"<scp>IĸBζ</scp> as a Central Modulator of Inflammatory Arthritis Pathogenesis","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: 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.","journal":"Arthritis & Rheumatology","year":2024,"id":471913,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9521,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1307060,"name":"Musarrat Naaz","orcid":null,"position":1,"is_corresponding":false},{"id":1251420,"name":"D. Mims","orcid":null,"position":2,"is_corresponding":false},{"id":617826,"name":"Prashant Gupta","orcid":"0009-0008-6291-9465","position":3,"is_corresponding":false},{"id":1251421,"name":"Timothy E. Peterson","orcid":null,"position":4,"is_corresponding":false},{"id":790368,"name":"Matthew Christopher","orcid":null,"position":5,"is_corresponding":false},{"id":245690,"name":"Srikanth Singamaneni","orcid":"0000-0002-7203-2613","position":6,"is_corresponding":false},{"id":230166,"name":"Gabriel Mbalaviele","orcid":"0000-0003-4660-0952","position":7,"is_corresponding":false},{"id":230168,"name":"Yousef Abu‐Amer","orcid":"0000-0002-5890-5086","position":8,"is_corresponding":false},{"id":230158,"name":"Gaurav Swarnkar","orcid":"0000-0001-6052-4971","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-19T02:05:48.788780Z","pmid":"39279148","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}