Abstract
Human and murine lymphocytes express dopamine (DA) D2-like receptors including DRD2, DRD3, and DRD4. However, their roles in rheumatoid arthritis (RA) are less clear. Here we showed that lymphocyte DRD2 activation alleviates both imbalance of T-helper (Th)17/T-regulatory (Treg) cells and inflamed symptoms in a mouse arthritis model of RA. Collagen-induced arthritis (CIA) was prepared by intradermal injection of chicken collagen type II (CII) in tail base of DBA/1 mice or Drd2 −/− C57BL/6 mice. D2-like receptor agonist quinpirole downregulated expression of proinflammatory Th17-related cytokines interleukin- (IL-) 17 and IL-22 but further upregulated expression of anti-inflammatory Treg-related cytokines transforming growth factor- (TGF-) β and IL-10 in lymphocytes in vitro and in ankle joints in vivo in CIA mice. Quinpirole intraperitoneal administration reduced both clinical arthritis score and serum anti-CII IgG level in CIA mice. However, Drd2 −/− CIA mice manifested more severe limb inflammation and higher serum anti-CII IgG level and further upregulated IL-17 and IL-22 expression and downregulated TGF-β and IL-10 expression than wild-type CIA mice. In contrast, Drd1 −/− CIA mice did not alter limb inflammation or anti-CII IgG level compared with wild-type CIA mice. These results suggest that DRD2 activation is involved in alleviation of CIA symptoms by amelioration of Th17/Treg imbalance.
Highlights
Dopamine (DA), a neurotransmitter in the central nervous system (CNS), has been found in the immune system [1, 2]
We firstly determined that D2-like receptor agonist quinpirole downregulated Th17 proinflammatory cytokine expression but upregulated Treg anti-inflammatory cytokine expression in Collagen-induced arthritis (CIA) mice in vitro; secondly we established that this agonist quinpirole ameliorated clinical symptoms and Th17/Treg imbalance in vivo in CIA mice; and lastly we demonstrated that Drd2-knockout (Drd2−/−) mice had more severe arthritic symptoms and Th17/Treg imbalance in CIA process
The expression of both the proinflammatory Th17-related cytokines IL-17 and IL-22 and the anti-inflammatory Tregrelated cytokines transforming growth factor- (TGF-)β and IL-10 was upregulated in CIA lymphocytes relative to that in intact lymphocytes in the presence of Con A (Figure 1(b))
Summary
Dopamine (DA), a neurotransmitter in the central nervous system (CNS), has been found in the immune system [1, 2] Both thymus and spleen express a dopaminergic system characterized by the presence of DA, vesicular monoamine transporters, and five subtypes of DA receptors [3]. The presence of these dopaminergic markers suggests that DA likely originating from immune cells and/or from sympathetic neuroeffector plexus is released in the lymphoid microenvironment [3]. Studies carried out on human and murine T cells have shown that stimulation of D1-like receptors impairs T cell function by causing the rise of intracellular cAMP levels [1]. Because Th17 and Treg cells are involved in autoimmunity as autoaggressive and BioMed Research International beneficial cells, respectively, it is likely that D1-like and D2like receptors expressed on T cells are involved in the interface between autoimmunity and health [1]
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