Spinal Tumor Center, Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, No. 415 Fengyang Road, Huangpu District, Shanghai, China.
East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Science and School of Life sciences, East China Normal University, 200241 Shanghai, China.
Pharmacol Res. 2021 Sep;171:105496. doi: 10.1016/j.phrs.2021.105496. Epub 2021 Feb 17.
Rheumatoid arthritis (RA) is an autoimmune disease mainly characterized as chronic inflammation of joint. Both genetic and environmental factors play important roles in RA progression. G protein-coupled receptor 54 (GPR54) and Kisspeptins (KPs), the natural GRP54 ligands encoded by Kiss-1 gene are known to play important roles in immune regulation but the precise role of KP-10/GPR54 in RA remains elusive. Kiss1/Gpr54 expression was determined by immunohistochemistry on protein and real-time PCR on RNA from isolated RA-patient synovial tissue and PBMC. Collagen-induced arthritis (CIA) mouse models were used to investigate the effect of KP-10/Gpr54 on the rheumatic arthritis severity in the mice. The signaling pathway involved in KP-10/GPR54 was assessed by western blot and immunofluorescence.In the present study, we demonstrated that GPR54 upregulation in bone marrow-derived macrophages (BMDM) was associated with the severity of RA. In addition, Gpr54 increased the inflammatory cytokines induced by lipopolysaccharide (LPS) in BMDM and diseased severity of CIA (n = 10), while KP-10 reduced the LPS-induced inflammatory cytokines in vitro and ameliorated the CIA symptoms in vivo. Furthermore, we demonstrated that KP-10/GPR54 binds to PP2A-C to suppressed LPS induced NF-κB and MAPK signaling in BMDM. All these findings suggest that KP-10/GPR54 may be a novel therapeutic target for the diagnosis and treatment of RA.
类风湿关节炎（RA）是一种主要以关节慢性炎症为特征的自身免疫性疾病。遗传和环境因素在 RA 的进展中都起着重要作用。G 蛋白偶联受体 54（GPR54）和 Kisspeptins（KPs），即 Kiss-1 基因编码的天然 GRP54 配体，已知在免疫调节中发挥重要作用，但 KP-10/GPR54 在 RA 中的确切作用仍不清楚。通过免疫组化在蛋白质和实时 PCR 在从分离的 RA 患者滑膜组织和 PBMC 中 RNA 上确定 Kiss1/Gpr54 的表达。使用胶原诱导性关节炎（CIA）小鼠模型来研究 KP-10/GPR54 对小鼠风湿性关节炎严重程度的影响。通过 Western blot 和免疫荧光评估涉及 KP-10/GPR54 的信号通路。在本研究中，我们证明了骨髓来源的巨噬细胞（BMDM）中 GPR54 的上调与 RA 的严重程度有关。此外，Gpr54 增加了 BMDM 中脂多糖（LPS）诱导的炎症细胞因子的产生和 CIA 的疾病严重程度（n=10），而 KP-10 减少了体外 LPS 诱导的炎症细胞因子，并改善了 CIA 症状体内。此外，我们证明 KP-10/GPR54 与 PP2A-C 结合，抑制 LPS 诱导的 BMDM 中 NF-κB 和 MAPK 信号。所有这些发现表明 KP-10/GPR54 可能是诊断和治疗 RA 的新治疗靶点。
