Paroxetine alleviates dendritic cell and T lymphocyte activation via GRK2-mediated PI3K–AKT signaling in rheumatoid arthritis

作者：Tingting Liu, Chao Jin, Jing Sun, Lina Zhu, Chun Wang, Feng Xiao, Xiaochang Liu, Liying Lv, Xiaoke Yang, Wenjing Zhou, Chao Tan, Xianli Wang, Wei Wei · 发表于：Chinese Medical Journal · 年份：2024 · DOI：10.1097/cm9.0000000000003165 · 被引用次数：13 · 研究领域：Receptor Mechanisms and Signaling、PI3K/AKT/mTOR signaling in cancer、Rheumatoid Arthritis Research and Therapies

BACKGROUND: 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). METHODS: 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. RESULTS: 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 ...