Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine, Medical Research Center, Seoul National University, Seoul, South Korea.
Division of Rheumatology, Department of Internal Medicine, College of Medicine, Seoul National University, Seoul, South Korea.
Ann Rheum Dis. 2018 Oct;77(10):1480-1489. doi: 10.1136/annrheumdis-2018-213444. Epub 2018 Jul 11.
Immune cells from patients with rheumatoid arthritis (RA) express more enolase-1 (ENO1) on their surface than those from healthy subjects, and they elicit an enhanced inflammatory response. This study is aimed to identify the ligands of ENO1 that could promote inflammatory loops in vitro and enhance the arthritis severity in vivo.
ENO1-binding proteins in RA synovial fluid were identified by mass spectromety, and affinity to ENO1 was evaluated by means of a ligand blotting and binding assay, surface plasmon resonance and confocal microscopy. Proinflammatory response by the interaction between ENO1 and apolipoprotein B (apoB) was tested in vitro and in vivo using peripheral blood mononuclear cells and a K/BxN serum transfer arthritis model and low-density lipoproteins receptor (LDLR) knockout mice.
ApoB in the synovid fluid of patients with RA was identified as a specific ligand to ENO1 with a higher affinity than plasminogen, a known ENO1 ligand. ApoB binding to ENO1 on monocytes elicited the production of tumour necrosis factor-α, interleukins (IL)-1β and IL-6 through both p38 mitogen-activated protein kinase and NF-κB pathways. In the K/BxN serum transfer arthritis model, administration of apoB increased the production of proinflammatory cytokines and exaggerated arthritis severity. The severity of K/BxN serum transfer arthritis in LDLR knockout mice was comparable with wild-type mice.
A key component of atherogenic lipids, apoB, aggravated arthritis by potentiating the inflammatory response its interaction with ENO1 expressed on the surface of immune cells. This suggests a novel mechanism by which lipid metabolism regulates chronic inflammation in RA.
类风湿关节炎（RA）患者的免疫细胞表面表达的烯醇化酶-1（ENO1）多于健康受试者，并且引发增强的炎症反应。本研究旨在鉴定可在体外促进炎症环并在体内增强关节炎严重程度的 ENO1 配体。
通过质谱法鉴定 RA 滑液中的 ENO1 结合蛋白，并通过配体印迹和结合测定、表面等离子体共振和共聚焦显微镜评估与 ENO1 的亲和力。使用外周血单核细胞和 K/BxN 血清转移关节炎模型以及低密度脂蛋白受体（LDLR）敲除小鼠，在体外和体内测试 ENO1 与载脂蛋白 B（apoB）之间的相互作用引起的促炎反应。
RA 患者滑液中的载脂蛋白 B 被鉴定为与 ENO1 具有更高亲和力的特定配体，其亲和力高于已知的 ENO1 配体纤溶酶原。载脂蛋白 B 与单核细胞上的 ENO1 结合通过 p38 有丝分裂原激活的蛋白激酶和 NF-κB 途径引发肿瘤坏死因子-α、白细胞介素（IL）-1β和 IL-6 的产生。在 K/BxN 血清转移关节炎模型中，载脂蛋白 B 的给药增加了促炎细胞因子的产生并加剧了关节炎的严重程度。LDLR 敲除小鼠的 K/BxN 血清转移关节炎的严重程度与野生型小鼠相当。
动脉粥样硬化脂质的关键成分载脂蛋白 B 通过增强其与免疫细胞表面表达的 ENO1 的炎症反应来加重关节炎。这表明脂质代谢调节 RA 中慢性炎症的新机制。
