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

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.