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

Abstract

AbstractBackgroundDopamine 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.MethodsDBA/1 mice and C57BL/6 mice with globalD1rorD2rdeficiency (D1r–/–orD2r–/–) or CD4+T cell-specificD2rdeletion (D2rfl/fl/CD4Cre) 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.ResultsCIA 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, whileD1r–/–CIA mice did not show the changes. CD4+T cell-specificD2rdeletion 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.ConclusionsD2R expressed on CD4+T cells is protective against imbalance between pro-inflammatory and anti-inflammatory T cells and arthritic symptoms in CIA.