Swarnkar Gaurav, Naaz Musarrat, Mims Dorothy, Gupta Prashant, Peterson Timothy, Christopher Matthew J, Singamaneni Srikanth, Mbalaviele Gabriel, Abu-Amer Yousef
Washington University School of Medicine, St. Louis, Missouri.
Washington University in St. Louis, Missouri.
Arthritis Rheumatol. 2025 Feb;77(2):124-139. doi: 10.1002/art.42990. Epub 2024 Oct 27.
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.
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.
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.
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.
目前针对炎症性关节炎中个体因素的疗法疗效各异，通常需要联合用药，且伴有不良副作用。核因子κB（NF-κB）对大多数炎性细胞因子的产生和功能至关重要。然而，鉴于其在生理过程中的重要作用，靶向NF-κB存在风险。因此，识别NF-κB下游在炎症性关节炎中选择性调控炎性细胞因子表达的信号通路将具有优势。我们之前已鉴定出IκBζ是NF-κB的一种独特炎性标志物，其仅在病理条件下控制炎性细胞因子的转录，同时保留生理NF-κB信号。
我们构建了髓系、淋巴系及全身Nfkbiz（编码IκBζ的基因）缺失的小鼠模型。这些模型接受血清转移诱导的关节炎实验。此外，腹腔注射IκBζ的药理学抑制剂。使用滑膜组织样本进行关节肿胀、微型计算机断层扫描、免疫组织化学、流式细胞术及细胞因子检测。
Nfkbiz的全身缺失或中性粒细胞（大量表达IκBζ的细胞）的耗竭减少了炎性滑膜细胞，增加了抗炎和再生性滑膜细胞，大幅降低了炎性因子的表达，并改善了实验性小鼠炎性关节炎。此外，滑膜细胞中负责衣康酸产生的免疫反应基因-1的表达增加。相应地，衣康酸衍生物二甲基衣康酸（DI）抑制了IκBζ介导的炎性因子。此外，计算机模拟筛选鉴定出8-羟基喹啉（HQ）是一种假定的IκBζ抑制剂，不影响生理NF-κB活性。同样地，全身给予DI或HQ均可抑制关节肿胀和损伤。
我们的研究将IκBζ定位为类风湿关节炎治疗中一个可考虑的炎症特异性靶点，因为对其抑制可保留NF-κB的有益功能。
