Dopamine D2 receptor on CD4+ T cells is protective against inflammatory responses and signs in a mouse model of rheumatoid arthritis

Xiao-Qin Wang; Huan-Huan Cai; Qiao-Wen Deng; Ya-Zhou Chang; Yu-Ping Peng; Yi-Hua Qiu

doi:10.1186/s13075-023-03071-1

Dopamine D2 receptor on CD4⁺ T cells is protective against inflammatory responses and signs in a mouse model of rheumatoid arthritis

Arthritis Res Ther. 2023 May 26;25(1):87. doi: 10.1186/s13075-023-03071-1.

Authors

Xiao-Qin Wang^#¹, Huan-Huan Cai^#¹, Qiao-Wen Deng^#¹, Ya-Zhou Chang², Yu-Ping Peng³, Yi-Hua Qiu⁴

Affiliations

¹ Department of Physiology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong, 226001, China.
² School of Medicine, Southeast University, Nanjing, 210009, China.
³ Department of Physiology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong, 226001, China. yppeng@ntu.edu.cn.
⁴ Department of Physiology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong, 226001, China. yhqiu@ntu.edu.cn.

^# Contributed equally.

Abstract

Background: Dopamine is a neurotransmitter and has been found to regulate lymphocytes by acting on dopamine receptors (DRs). CD4⁺ T cells express all the five subtypes of DRs, D1R to D5R. Although CD4⁺ T cells have been involved in pathogenesis of rheumatoid arthritis (RA), roles of DRs expressed on these cells in RA are poorly understood. This study determined whether D2R expressed on CD4⁺ T cells regulates inflammatory responses and signs in collagen type II (CII)-induced arthritis (CIA), a mouse model of RA.

Methods: DBA/1 mice and C57BL/6 mice with global D1r or D2r deficiency (D1r^-/- or D2r^-/-) or CD4⁺ T cell-specific D2r deletion (D2r^fl/fl/CD4^Cre) were used to prepare CIA model by intradermal injection of CII. D2R agonist sumanirole was intraperitoneally administered in CIA mice. CD4⁺ T cells obtained from CIA mice were exposed to sumanirole or/and D2R antagonist L-741,626 in vitro. Arthritic symptoms were assessed by clinical arthritis scores. Flow cytometric assay measured frequencies of CD4⁺ T cell subsets (Th1, Th2, Th17 and Treg cells). Expression of specific transcription factors for the CD4⁺ T cell subsets was tested by Western blot. Cytokine production was estimated by quantitative PCR and ELISA.

Results: CIA mice manifested a bias of CD4⁺ T cells towards Th1 and Th17 cells. D2r^-/- CIA mice showed a stronger bias towards Th1 and Th17 phenotypes than CIA mice, while D1r^-/- CIA mice did not show the changes. CD4⁺ T cell-specific D2r deletion exacerbated both the polarization towards Th1 and Th17 cells and the symptoms of arthritis. Sumanirole administration in CIA mice ameliorated the bias of CD4⁺ T cells towards Th1 and Th17 phenotypes as well as arthritic symptoms. Sumanirole treatment of in vitro CD4⁺ T cells obtained from CIA mice promoted the shift to Treg cells, and the effect of sumanirole was blocked by L-741,626.

Conclusions: D2R expressed on CD4⁺ T cells is protective against imbalance between pro-inflammatory and anti-inflammatory T cells and arthritic symptoms in CIA.

Keywords: CD4+ T cells; Collagen-induced arthritis; D2r fl/fl /CD4 Cre mice; Dopamine D2 receptor; Rheumatoid arthritis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arthritis, Experimental* / metabolism
Arthritis, Rheumatoid* / drug therapy
Disease Models, Animal
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Receptors, Dopamine D2* / metabolism
T-Lymphocytes, Regulatory / metabolism
Th17 Cells / metabolism

Substances

Receptors, Dopamine D2
DRD2 protein, mouse