Department of Materials Science and Engineering, Yonsei University, Seoul, South Korea.
Division of Rheumatology, Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, South Korea.
Front Immunol. 2022 Aug 11;13:961197. doi: 10.3389/fimmu.2022.961197. eCollection 2022.
Although recent studies have demonstrated a proinflammatory effect of extracellular histones in sepsis endothelial cytotoxicity, little is known about their contribution to autoimmune arthritis. Therefore, we investigated the role of extracellular histones in autoimmune arthritis and their cytotoxic effect on synoviocytes and macrophages. We measured histones in the synovial fluid of patients with rheumatoid arthritis (RA) and evaluated arthritis severity in a serum-transfer arthritis (STA) mouse model with intraperitoneal histone injection. Histone-induced cytotoxicity was measured using SYTOX green staining in the synoviocyte cell line MH7A and macrophages differentiated from the monocytic cell line THP-1, and the production of damage-associated molecular patterns (DAMPs) was measured by HMGB1 and ATP. Furthermore, we performed RNA-seq analysis of THP-1 cells stimulated with H2B-α1 peptide or with its citrullinated form. The levels of histones were elevated in RA synovial fluid, and histones aggravated arthritis in the STA model. Histones induced cytotoxicity and DAMP production in synoviocytes and macrophages. Chondroitin sulfate reduced histone-induced cytotoxicity, while lipopolysaccharides aggravated cytotoxicity. Moreover, the cytotoxicity decreased when the arginines in H2B-α1 were replaced with citrullines, which demonstrated its electrostatic nature. In transcriptome analysis, H2B-α1 changed the gene expression pattern of THP-1 cells involving chemokines, interleukin-1, -4, -10, -13, and toll-like receptor (TLR) signaling pathways. Extracellular histones were increased in RA synovial fluid and aggravated synovitis in STA. They induced lytic cell death through electrostatic interaction with synoviocytes and macrophages, leading to the secretion of DAMPs. These findings suggest that histones play a central role in autoimmune arthritis.
虽然最近的研究表明细胞外组蛋白在脓毒症中的促炎作用与内皮细胞毒性有关，但它们在自身免疫性关节炎中的作用知之甚少。因此，我们研究了细胞外组蛋白在自身免疫性关节炎中的作用及其对滑膜细胞和巨噬细胞的细胞毒性作用。我们测量了类风湿关节炎（RA）患者滑液中的组蛋白，并通过腹腔内注射组蛋白评估了血清转移关节炎（STA）小鼠模型中的关节炎严重程度。通过 SYTOX 绿染色测量了 MH7A 滑膜细胞系和从单核细胞系 THP-1 分化的巨噬细胞中的组蛋白诱导的细胞毒性，并通过 HMGB1 和 ATP 测量了损伤相关分子模式（DAMP）的产生。此外，我们对用 H2B-α1 肽或其瓜氨酸化形式刺激的 THP-1 细胞进行了 RNA-seq 分析。RA 滑液中的组蛋白水平升高，组蛋白加剧了 STA 模型中的关节炎。组蛋白诱导了滑膜细胞和巨噬细胞的细胞毒性和 DAMP 产生。硫酸软骨素降低了组蛋白诱导的细胞毒性，而脂多糖则加重了细胞毒性。此外，当 H2B-α1 中的精氨酸被瓜氨酸取代时，细胞毒性降低，这表明其具有静电性质。在转录组分析中，H2B-α1 改变了 THP-1 细胞的基因表达模式，涉及趋化因子、白细胞介素-1、-4、-10、-13 和 Toll 样受体（TLR）信号通路。RA 滑液中的细胞外组蛋白增加，并加重 STA 中的滑膜炎。它们通过与滑膜细胞和巨噬细胞的静电相互作用诱导裂解细胞死亡，导致 DAMPs 的分泌。这些发现表明组蛋白在自身免疫性关节炎中起核心作用。
