Lee Jung-Eun, Im Dong-Soon
Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02446, Republic of Korea.
Department of Basic Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02446, Republic of Korea.
Int J Mol Sci. 2025 May 14;26(10):4680. doi: 10.3390/ijms26104680.
Lysophosphatidylinositols are degradation products of phosphatidylinositols within cell membranes and digestive metabolites of a high-fat diet in the gut. G-protein-coupled receptor 55 (GPR55) is a receptor that senses lysophosphatidylinositol and acts as an immune mediator, being primarily upregulated during immune cell activation. This study aimed to investigate the role of GPR55, using its antagonist, CID16020046, in a collagen-induced rheumatoid arthritis mouse model. It was observed that DBA-1J mice develop joint lesions characteristic of rheumatoid arthritis following immunization with bovine type II collagen. The administration of CID16020046 (1 mg/kg, intraperitoneally) alleviated rheumatoid arthritis symptoms and inflammatory responses. Histopathological analysis showed that CID16020046 reduced foot edema, proteoglycan loss, and bone erosion in the joints. CID16020046 also decreased rheumatoid-arthritis-induced serum IgG levels, as measured using enzyme-linked immunosorbent assays. The treatment reduced levels of pro-inflammatory cytokines (IL-1β and IL-6), Th1 cytokine (IFN-γ), and Th17 cytokine (IL-17A), along with matrix metalloproteinase-3 (MMP-3) and the receptor activator of nuclear factor-κB ligand (RANKL) in the feet. A significant reduction in splenomegaly was also observed, along with significant reductions in CD4 T helper 1 (Th1) and Th17 cells in the spleen. Additionally, CID16020046 suppressed the differentiation of naïve T cells into CD4IL-17 Th17 cells. CID16020046 suppressed expression levels of inflammatory cytokine mRNAs in SW982 human synovial cells. In conclusion, blocking GPR55 alleviates collagen-induced rheumatoid arthritis symptoms by suppressing Th1 and Th17 cells in the spleen and pro-inflammatory cytokines in the joints, suggesting that GPR55 is a potential therapeutic target for autoimmune inflammatory diseases.
溶血磷脂酰肌醇是细胞膜内磷脂酰肌醇的降解产物以及肠道中高脂饮食的消化代谢产物。G蛋白偶联受体55（GPR55）是一种感知溶血磷脂酰肌醇并作为免疫介质发挥作用的受体，在免疫细胞激活过程中主要上调。本研究旨在使用其拮抗剂CID16020046，在胶原诱导的类风湿性关节炎小鼠模型中研究GPR55的作用。观察到DBA-1J小鼠在用牛II型胶原免疫后出现类风湿性关节炎特征性的关节病变。腹腔注射CID16020046（1mg/kg）可减轻类风湿性关节炎症状和炎症反应。组织病理学分析表明，CID16020046可减轻足部水肿、蛋白聚糖丢失和关节骨侵蚀。使用酶联免疫吸附测定法测量，CID16020046还可降低类风湿性关节炎诱导的血清IgG水平。该治疗降低了促炎细胞因子（IL-1β和IL-6）、Th1细胞因子（IFN-γ）和Th17细胞因子（IL-17A）的水平，以及足部基质金属蛋白酶-3（MMP-3）和核因子κB受体激活剂配体（RANKL）的水平。还观察到脾肿大显著减轻，同时脾脏中CD4辅助性T细胞1（Th1）和Th17细胞显著减少。此外，CID16020046抑制了幼稚T细胞向CD4IL-17 Th17细胞的分化。CID16020046抑制了SW982人滑膜细胞中炎性细胞因子mRNA的表达水平。总之，阻断GPR55可通过抑制脾脏中的Th1和Th17细胞以及关节中的促炎细胞因子来减轻胶原诱导的类风湿性关节炎症状，这表明GPR55是自身免疫性炎症疾病的潜在治疗靶点。
