Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Clin Immunol. 2024 Jul;264:110255. doi: 10.1016/j.clim.2024.110255. Epub 2024 May 18.
Fibroblast-like synoviocytes (FLS) play critical roles in rheumatoid arthritis (RA). Itaconate (ITA), an endogenous metabolite derived from the tricarboxylic acid (TCA) cycle, has attracted attention because of its anti-inflammatory, antiviral, and antimicrobial effects. This study evaluated the effect of ITA on FLS and its potential to treat RA. ITA significantly decreased FLS proliferation and migration in vitro, as well as mitochondrial oxidative phosphorylation and glycolysis measured by an extracellular flux analyzer. ITA accumulates metabolites including succinate and citrate in the TCA cycle. In rats with type II collagen-induced arthritis (CIA), intra-articular injection of ITA reduced arthritis and bone erosion. Irg1-deficient mice lacking the ability to produce ITA had more severe arthritis than control mice in the collagen antibody-induced arthritis. ITA ameliorated CIA by inhibiting FLS proliferation and migration. Thus, ITA may be a novel therapeutic agent for RA.
成纤维样滑膜细胞（FLS）在类风湿关节炎（RA）中发挥着关键作用。衣康酸（ITA）是一种源自三羧酸（TCA）循环的内源性代谢物，因其具有抗炎、抗病毒和抗菌作用而受到关注。本研究评估了 ITA 对 FLS 的作用及其治疗 RA 的潜力。ITA 显著抑制了体外 FLS 的增殖和迁移，以及通过细胞外通量分析仪测量的线粒体氧化磷酸化和糖酵解。ITA 在 TCA 循环中积累了包括琥珀酸和柠檬酸在内的代谢物。在Ⅱ型胶原诱导的关节炎（CIA）大鼠中，关节内注射 ITA 可减轻关节炎和骨侵蚀。缺乏产生 ITA 能力的 Irg1 缺陷型小鼠在胶原抗体诱导的关节炎中比对照小鼠的关节炎更严重。ITA 通过抑制 FLS 的增殖和迁移来改善 CIA。因此，ITA 可能成为 RA 的一种新型治疗药物。
