Liu Tingting, Jin Chao, Sun Jing, Zhu Lina, Wang Chun, Xiao Feng, Liu Xiaochang, Lv Liying, Yang Xiaoke, Zhou Wenjing, Tan Chao, Wang Xianli, Wei Wei
Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China.
The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, Anhui 230022, China.
Chin Med J (Engl). 2025 Feb 20;138(4):441-451. doi: 10.1097/CM9.0000000000003165. Epub 2024 Jun 14.
G protein-coupled receptor kinase 2 (GRK2) could participate in the regulation of diverse cells via interacting with non-G-protein-coupled receptors. In the present work, we explored how paroxetine, a GRK2 inhibitor, modulates the differentiation and activation of immune cells in rheumatoid arthritis (RA).
The blood samples of healthy individuals and RA patients were collected between July 2021 and March 2022 from the First Affiliated Hospital of Anhui Medical University. C57BL/6 mice were used to induce the collagen-induced arthritis (CIA) model. Flow cytometry analysis was used to characterize the differentiation and function of dendritic cells (DCs)/T cells. Co-immunoprecipitation was used to explore the specific molecular mechanism.
In patients with RA, high expression of GRK2 in peripheral blood lymphocytes, accompanied by the increases of phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR). In animal model, a decrease in regulatory T cells (T regs ), an increase in the cluster of differentiation 8 positive (CD8 + ) T cells, and maturation of DCs were observed. Paroxetine, when used in vitro and in CIA mice, restrained the maturation of DCs and the differentiation of CD8 + T cells, and induced the proportion of T regs . Paroxetine inhibited the secretion of pro-inflammatory cytokines, the expression of C-C motif chemokine receptor 7 in DCs and T cells. Simultaneously, paroxetine upregulated the expression of programmed death ligand 1, and anti-inflammatory cytokines. Additionally, paroxetine inhibited the PI3K-AKT-mTOR metabolic pathway in both DCs and T cells. This was associated with a reduction in mitochondrial membrane potential and changes in the utilization of glucose and lipids, particularly in DCs. Paroxetine reversed PI3K-AKT pathway activation induced by 740 Y-P (a PI3K agonist) through inhibiting the interaction between GRK2 and PI3K in DCs and T cells.
Paroxetine exerts an immunosuppressive effect by targeting GRK2, which subsequently inhibits the metabolism-related PI3K-AKT-mTOR pathway of DCs and T cells in RA.
G蛋白偶联受体激酶2（GRK2）可通过与非G蛋白偶联受体相互作用参与多种细胞的调节。在本研究中，我们探讨了GRK2抑制剂帕罗西汀如何调节类风湿关节炎（RA）中免疫细胞的分化和活化。
2021年7月至2022年3月期间，从安徽医科大学第一附属医院收集健康个体和RA患者的血液样本。使用C57BL/6小鼠诱导胶原诱导性关节炎（CIA）模型。采用流式细胞术分析来表征树突状细胞（DCs）/T细胞的分化和功能。采用免疫共沉淀法探讨具体分子机制。
在RA患者中，外周血淋巴细胞中GRK2高表达，同时磷脂酰肌醇3激酶（PI3K）、蛋白激酶B（AKT）和雷帕霉素靶蛋白（mTOR）增加。在动物模型中，观察到调节性T细胞（Tregs）减少，分化簇8阳性（CD8+）T细胞增加，以及DCs成熟。帕罗西汀在体外和CIA小鼠中使用时，可抑制DCs成熟和CD8+T细胞分化，并诱导Tregs比例增加。帕罗西汀抑制促炎细胞因子的分泌、DCs和T细胞中C-C基序趋化因子受体7的表达。同时，帕罗西汀上调程序性死亡配体1和抗炎细胞因子的表达。此外，帕罗西汀抑制DCs和T细胞中的PI3K-AKT-mTOR代谢途径。这与线粒体膜电位降低以及葡萄糖和脂质利用的变化有关，尤其是在DCs中。帕罗西汀通过抑制DCs和T细胞中GRK2与PI3K之间的相互作用，逆转了740 Y-P（一种PI3K激动剂）诱导的PI3K-AKT途径激活。
帕罗西汀通过靶向GRK2发挥免疫抑制作用，随后抑制RA中DCs和T细胞的代谢相关PI3K-AKT-mTOR途径。
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