Zhu Xiaoying, Lu Hanya, Jia Haonan, Wei Xuemin, Xue Jiawei, Li Wenjing, Zhang Juan, Wang Yanli, Yan Jingyao, Sun Haoyuan, Ge Yanlei, Zhang Zhiyi
Department of Rheumatology, First Affiliated Hospital of Harbin Medical University, Harbin, China.
Department of Osteology, Heilongjiang Provincial Hospital, Harbin, China.
J Transl Med. 2025 Mar 6;23(1):280. doi: 10.1186/s12967-025-06300-0.
Rheumatoid arthritis (RA) is a systemic chronic autoimmune disease with complex mechanism. Currently, ferroptosis is believed to play a role in it, but the specific mechanism is unknown, especially in immune response. In this study, we demonstrated that the high expression of major histocompatibility complex I (MHC-I) molecules in RA fibroblast-like synoviocytes (FLSs) is an antigen-presenting cell property and that this property is closely related to the increase in antigens after citrullination. Moreover, we detected higher levels of ferroptosis among FLSs from RA patient than among FLSs from OA patients. Ferroptosis can increase the expression of citrullinated histone H3 (cit-h3) by promoting the production of peptidyl arginine deiminase 4 (PAD4), which further promotes the expression of MHC-I molecules. We cocultured RA-FLSs treated with ferroptosis drugs with selected CD8 + T cells to assess the effect of ferroptosis on the endogenous antigen-presenting function of RA-FLSs. Ferroptosis promoted the proliferation of CD8 + T cells and the release of the inflammatory factors Tumor necrosis factor-α (TNF-α) and Interferon-gamma (IFN-γ), which enhanced the inflammatory effect. This phenomenon was also observed in a collagen-induced arthritis (CIA) mouse model. Finally, ferrostatin-1 (fer-1), a ferroptosis inhibitor, inhibited the above effects and reduced the release of inflammatory factors, indicating that ferroptosis may play a therapeutic role in RA and providing new ideas for the treatment of RA in the field of immunity.
类风湿关节炎（RA）是一种机制复杂的全身性慢性自身免疫性疾病。目前，铁死亡被认为在其中发挥作用，但其具体机制尚不清楚，尤其是在免疫反应方面。在本研究中，我们证明类风湿关节炎成纤维样滑膜细胞（FLS）中主要组织相容性复合体I（MHC-I）分子的高表达是一种抗原呈递细胞特性，且该特性与瓜氨酸化后抗原的增加密切相关。此外，我们检测到类风湿关节炎患者FLS中的铁死亡水平高于骨关节炎患者FLS中的铁死亡水平。铁死亡可通过促进肽基精氨酸脱亚氨酶4（PAD4）的产生来增加瓜氨酸化组蛋白H3（cit-h3）的表达，进而促进MHC-I分子的表达。我们将用铁死亡药物处理的类风湿关节炎FLS与选定的CD8 + T细胞共培养，以评估铁死亡对类风湿关节炎FLS内源性抗原呈递功能的影响。铁死亡促进了CD8 + T细胞的增殖以及炎性因子肿瘤坏死因子-α（TNF-α）和干扰素-γ（IFN-γ）的释放，从而增强了炎症效应。在胶原诱导的关节炎（CIA）小鼠模型中也观察到了这种现象。最后，铁死亡抑制剂铁抑素-1（fer-1）抑制了上述效应并减少了炎性因子的释放，这表明铁死亡可能在类风湿关节炎中发挥治疗作用，并为免疫领域类风湿关节炎的治疗提供了新思路。
