Xue Meilang, Lin Haiyan, Liang Hai Po Helena, Bereza-Malcolm Lara, Lynch Tom, Sinnathurai Premarani, Weiler Hartmut, Jackson Christopher, March Lyn
Sutton Arthritis Research Laboratory, Sydney Musculoskeletal Health, Kolling Institute, Faculty of Medicine and Health, The University of Sydney and the Northern Sydney Local Health District, Sydney, NSW, Australia.
Australian Arthritis and Autoimmune Biobank Collaborative (A3BC), Sydney Musculoskeletal Health, Kolling Institute, Faculty of Medicine and Health, The University of Sydney and the Northern Sydney Local Health District, Sydney, NSW, Australia.
Rheumatology (Oxford). 2024 Feb 1;63(2):571-580. doi: 10.1093/rheumatology/kead230.
Endothelial protein C receptor (EPCR) is highly expressed in synovial tissues of patients with RA, but the function of this receptor remains unknown in RA. This study investigated the effect of EPCR on the onset and development of inflammatory arthritis and its underlying mechanisms.
CIA was induced in EPCR gene knockout (KO) and matched wild-type (WT) mice. The onset and development of arthritis was monitored clinically and histologically. T cells, dendritic cells (DCs), EPCR and cytokines from EPCR KO and WT mice, RA patients and healthy controls (HCs) were detected by flow cytometry and ELISA.
EPCR KO mice displayed >40% lower arthritis incidence and 50% less disease severity than WT mice. EPCR KO mice also had significantly fewer Th1/Th17 cells in synovial tissues with more DCs in circulation. Lymph nodes and synovial CD4 T cells from EPCR KO mice expressed fewer chemokine receptors CXCR3, CXCR5 and CCR6 than WT mice. In vitro, EPCR KO spleen cells contained fewer Th1 and more Th2 and Th17 cells than WT and, in concordance, blocking EPCR in WT cells stimulated Th2 and Th17 cells. DCs generated from EPCR KO bone marrow were less mature and produced less MMP-9. Circulating T cells from RA patients expressed higher levels of EPCR than HC cells; blocking EPCR stimulated Th2 and Treg cells in vitro.
Deficiency of EPCR ameliorates arthritis in CIA via inhibition of the activation and migration of pathogenic Th cells and DCs. Targeting EPCR may constitute a novel strategy for future RA treatment.
内皮蛋白C受体（EPCR）在类风湿关节炎（RA）患者的滑膜组织中高表达，但该受体在RA中的功能尚不清楚。本研究探讨EPCR对炎性关节炎发病和发展的影响及其潜在机制。
在EPCR基因敲除（KO）小鼠和匹配的野生型（WT）小鼠中诱导胶原诱导性关节炎（CIA）。通过临床和组织学监测关节炎的发病和发展。采用流式细胞术和酶联免疫吸附测定法检测EPCR KO小鼠、WT小鼠、RA患者和健康对照（HC）的T细胞、树突状细胞（DC）、EPCR和细胞因子。
与WT小鼠相比，EPCR KO小鼠的关节炎发病率降低>40%，疾病严重程度降低50%。EPCR KO小鼠滑膜组织中的Th1/Th17细胞也明显减少，循环中的DC增多。与WT小鼠相比，EPCR KO小鼠的淋巴结和滑膜CD4 T细胞表达的趋化因子受体CXCR3、CXCR5和CCR6更少。在体外，EPCR KO脾细胞中的Th1细胞比WT细胞少，Th2和Th17细胞更多，同样，阻断WT细胞中的EPCR可刺激Th2和Th17细胞。由EPCR KO骨髓产生的DC成熟度较低，MMP-9产生较少。RA患者的循环T细胞表达的EPCR水平高于HC细胞；阻断EPCR在体外刺激Th2和调节性T细胞。
EPCR缺乏通过抑制致病性Th细胞和DC的激活和迁移改善CIA中的关节炎。靶向EPCR可能成为未来RA治疗的新策略。
