Zheng Yanan, Wang Yumeng, Xu Yujie, Shen Shanshan, Xu Haozhe, Hu Chao, Chen Yongzhen, Teng Fengmeng, Pan Jinshun, Zheng Shuqian, Wang Junqi, Su Zhongping, You Qiang
Department of Geriatrics, Department of Biotherapy, the Second Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, 210011, China.
Department of Surgery, the Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 210031, China.
Mol Med. 2025 May 14;31(1):187. doi: 10.1186/s10020-025-01248-9.
GPR84 is a Gi-coupled G-protein-coupled receptor (GPCR) predominantly expressed in immune cells, with its expression upregulated during inflammatory conditions. However, its specific role in immune-mediated liver injury remains unclear.
We utilized a concanavalin A (Con A)-induced mouse model to simulate immune-mediated liver injury. The expression of GPR84 was assessed by quantitative RT-PCR and western blotting. GPR84 gene knockout mice were employed to evaluate the receptor's functional role. Bone marrow chimeric mice were created to determine the involvement of hematopoietic cells. Infiltrating liver inflammatory cells were analyzed by flow cytometry. The activation of key signaling pathways in hepatic tissues was assessed by western blotting. The GPR84 antagonist GLPG1205 was tested in this model to evaluate its therapeutic potential.
GPR84 expression was significantly upregulated in the mouse liver following Con A injection. Mice lacking GPR84 exhibited reduced serum ALT and AST levels, diminished liver damage, and decreased apoptosis. Additionally, the expression levels of inflammatory cytokines MCP-1 and TNF-α were significantly lower in Gpr84 mice compared to wild-type (WT) mice after Con A injection. Flow cytometry analysis revealed a notable reduction in the proportion of Kupffer cells and infiltrating monocytes (CD11b⁺Ly6CLy6G⁻) in Gpr84 mice. Using bone marrow chimeric mice, we demonstrated that GPR84-deficient bone marrow-derived cells mitigate Con A-induced liver injury. Furthermore, GPR84 deficiency was associated with reduced hepatic apoptosis and lower phosphorylation levels of STAT3, ERK, JNK, p38, and p65, effectively inhibiting key inflammatory signaling pathways. Importantly, treatment with the GPR84 antagonist GLPG1205 significantly lowered serum ALT and AST levels, reduced the expression of inflammatory cytokines, and alleviated liver damage.
Our findings suggest that GPR84 plays a pivotal role in immune-mediated liver injury, primarily through its expression on hematopoietic cells. Targeting GPR84, particularly with the antagonist GLPG1205, offers a promising therapeutic strategy for treating immune-related liver diseases.
GPR84是一种与Gi偶联的G蛋白偶联受体（GPCR），主要在免疫细胞中表达，在炎症状态下其表达上调。然而，其在免疫介导的肝损伤中的具体作用仍不清楚。
我们利用刀豆蛋白A（Con A）诱导的小鼠模型来模拟免疫介导的肝损伤。通过定量RT-PCR和蛋白质印迹法评估GPR84的表达。使用GPR84基因敲除小鼠来评估该受体的功能作用。构建骨髓嵌合小鼠以确定造血细胞的参与情况。通过流式细胞术分析浸润肝脏的炎性细胞。通过蛋白质印迹法评估肝组织中关键信号通路的激活情况。在此模型中测试GPR84拮抗剂GLPG1205以评估其治疗潜力。
Con A注射后，小鼠肝脏中GPR84的表达显著上调。缺乏GPR84的小鼠血清ALT和AST水平降低，肝损伤减轻，细胞凋亡减少。此外，Con A注射后，Gpr84小鼠中炎性细胞因子MCP-1和TNF-α的表达水平明显低于野生型（WT）小鼠。流式细胞术分析显示，Gpr84小鼠中库普弗细胞和浸润单核细胞（CD11b⁺Ly6CLy6G⁻）的比例显著降低。利用骨髓嵌合小鼠，我们证明了GPR84缺陷的骨髓来源细胞可减轻Con A诱导的肝损伤。此外，GPR84缺陷与肝细胞凋亡减少以及STAT3、ERK、JNK、p38和p65的磷酸化水平降低有关，有效抑制了关键的炎症信号通路。重要的是，用GPR84拮抗剂GLPG1205治疗可显著降低血清ALT和AST水平，减少炎性细胞因子的表达，并减轻肝损伤。
我们的研究结果表明，GPR84在免疫介导的肝损伤中起关键作用，主要通过其在造血细胞上的表达。靶向GPR84，特别是使用拮抗剂GLPG1205，为治疗免疫相关肝病提供了一种有前景的治疗策略。
