可溶性内皮蛋白 C 受体在类风湿关节炎中的水平升高，并阻断蛋白 C 在胶原诱导性关节炎中的治疗作用。
Elevated levels of soluble Endothelial protein C receptor in rheumatoid arthritis and block the therapeutic effect of protein C in collagen-induced arthritis.
机构信息
Department of Rheumatology, The First Affiliated Hospital of Baotou Medical College, Baotou 014010, China; Institute of Immunology and Rheumatology, Baotou Medical College (Inner Mongolia Key Laboratory of Autoimmunity), Baotou 014010, China; Baotou Medical College, Baotou 014010, China.
Department of Rheumatology, The First Affiliated Hospital of Baotou Medical College, Baotou 014010, China; Baotou Medical College, Baotou 014010, China.
出版信息
Int Immunopharmacol. 2020 Apr;81:106255. doi: 10.1016/j.intimp.2020.106255. Epub 2020 Jan 30.
BACKGROUND
Endothelial protein C receptor (EPCR) is a membranous protein that can be combined with a variety of ligands and plays important roles in anticoagulant and anti-inflammation. Recent reports have shown that surface EPCR expression on T cells is negatively associated with Th17 differentiation and is co-expressed with other immunosuppressive molecules, such as The programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). Hence, we hypothesized that EPCR may play a critical role in rheumatoid arthritis (RA) disease progression that is mediated by Th17 differentiation. In order to explore the role of EPCR on RA disease pathogenesis, we detected membranous EPCR (mEPCR) expression in CD4 T cells and soluble EPCR (sEPCR) expression in the sera of RA patients.
METHODS
The proportion of CD4/EPCR T cells in the peripheral blood of RA patients was detected by flow cytometry, and the expression of sEPCR in the sera of RA patients was detected by enzyme-linked immunosorbent assay (ELISA). For in vitro experiments, protein C (PC) and EPCR recombinant proteins were used to block peripheral blood mononuclear cell (PBMC) activation and to detect Th17 differentiation. For in vivo experiments in DBA/1 mice with collagen-induced arthritis (CIA), we administered PC and EPCR recombinant proteins, monitored disease progression, and evaluated the role of EPCR in disease progression.
RESULTS
The proportion of CD4/EPCR T cells in the peripheral blood of RA patients was lower than that of osteoarthritis (OA) patients, while the expression level of sEPCR in the sera of RA patients was concomitantly higher than that in OA patients. Subsequent analysis revealed that sEPCR expression was positively correlated with rheumatoid factors (RF) and other inflammatory indicators in RA patients. Further studies confirmed that sEPCR administration alleviated the progression of collagen-induced arthritis and partially blocked the therapeutic effect of PC in CIA mice.
CONCLUSION
Soluble EPCR is associated with RA disease progression and induces disease remission in CIA mice by inhibiting Th17 differentiation.
背景
内皮蛋白 C 受体（EPCR）是一种膜蛋白，可与多种配体结合，在抗凝和抗炎中发挥重要作用。最近的报告表明，T 细胞表面 EPCR 的表达与 Th17 分化呈负相关，并与其他免疫抑制分子共表达，如程序性细胞死亡 1（PD-1）和细胞毒性 T 淋巴细胞相关抗原-4（CTLA-4）。因此，我们假设 EPCR 可能在 Th17 分化介导的类风湿关节炎（RA）疾病进展中发挥关键作用。为了探讨 EPCR 在 RA 发病机制中的作用，我们检测了 RA 患者外周血 CD4 T 细胞中的膜性 EPCR（mEPCR）表达和血清中的可溶性 EPCR（sEPCR）表达。
方法
通过流式细胞术检测 RA 患者外周血中 CD4/EPCR T 细胞的比例，通过酶联免疫吸附试验（ELISA）检测 RA 患者血清中 sEPCR 的表达。体外实验中，用蛋白 C（PC）和 EPCR 重组蛋白阻断外周血单个核细胞（PBMC）的激活，检测 Th17 分化。在胶原诱导关节炎（CIA）的 DBA/1 小鼠体内实验中，我们给予 PC 和 EPCR 重组蛋白，监测疾病进展，并评估 EPCR 在疾病进展中的作用。
结果
RA 患者外周血中 CD4/EPCR T 细胞的比例低于骨关节炎（OA）患者，而 RA 患者血清中 sEPCR 的表达水平也高于 OA 患者。进一步分析显示，sEPCR 的表达与 RA 患者的类风湿因子（RF）和其他炎症指标呈正相关。进一步的研究证实，sEPCR 的给药缓解了胶原诱导关节炎的进展，并部分阻断了 PC 在 CIA 小鼠中的治疗作用。
结论
可溶性 EPCR 与 RA 疾病进展相关，并通过抑制 Th17 分化诱导 CIA 小鼠疾病缓解。
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