Paroxetine alleviates dendritic cell and T lymphocyte activation via GRK2-mediated PI3K-AKT signaling in rheumatoid arthritis.
10.1097/CM9.0000000000003165
- Author:
Tingting LIU
1
;
Chao JIN
2
;
Jing SUN
1
;
Lina ZHU
3
;
Chun WANG
4
;
Feng XIAO
4
;
Xiaochang LIU
5
;
Liying LV
6
;
Xiaoke YANG
7
;
Wenjing ZHOU
1
;
Chao TAN
1
;
Xianli WANG
8
;
Wei WEI
4
Author Information
1. Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China.
2. Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China.
3. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China.
4. Institute of Clinical Pharmacology, Anhui Medical University, The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui 230032, China.
5. Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China.
6. Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China.
7. Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China.
8. Department of Pharmacy, The Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200090, China.
- Publication Type:Journal Article
- MeSH:
G-Protein-Coupled Receptor Kinase 2/metabolism*;
Arthritis, Rheumatoid/immunology*;
Animals;
Dendritic Cells/metabolism*;
Paroxetine/therapeutic use*;
Proto-Oncogene Proteins c-akt/metabolism*;
Mice;
Humans;
Mice, Inbred C57BL;
Signal Transduction/drug effects*;
Male;
Phosphatidylinositol 3-Kinases/metabolism*;
Lymphocyte Activation/drug effects*;
Female;
T-Lymphocytes/metabolism*;
Middle Aged
- From:
Chinese Medical Journal
2025;138(4):441-451
- CountryChina
- Language:English
-
Abstract:
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 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.
CONCLUSION: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.
