Dopamine D2 Receptor Is Involved in Alleviation of Type II Collagen-Induced Arthritis in Mice

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.

Dopamine D2 receptor restricts astrocytic NLRP3 inflammasome activation via enhancing the interaction of β-arrestin2 and NLRP3

“…Drd2 agonist was first reported to suppress nitric oxide and tumor necrosis factor-α in peripheral neutrophils two decades ago [32]. Since then, more studies have showed that Drd2 is a potential candidate for amelioration of inflammatory diseases [33][34][35][36] and NDDs [22,[37][38][39]. Nevertheless, to date there are no reports on whether Drd2 participates in the suppression of inflammasome activation.…”

Repeated administration of mazindol reduces spontaneous pain-related behaviors without modifying bone density and microarchitecture in a mouse model of complete Freund’s adjuvant-induced knee arthritis

“…Recent studies have shown that dopamine acting through its receptors is involved in the pathogenesis of RA. 9 , 10 Dopamine receptors are seven-transmembrane G-coupled receptors and, so far, five subtypes have been reported to exist. 11 – 13 D1 and D5 receptors are D1-like receptors, whereas D2–D4 are D2-like receptors.…”

“… 11 – 13 Anatomic studies have demonstrated the expression of dopamine in dendritic cells in the synovial tissue from patients with RA, as well as the expression of D1–D5 receptors on B cells and fibroblasts from patients with RA. 10 , 14 Interestingly, a study 14 has shown an increased expression of D2-like receptors on B cells in synovial fluids from RA patients, and administration of a D2-like receptor agonist decreased arthritic scores in mice with collagen-induced RA. 10 , 15 Moreover, both administration of D2-like receptor antagonist and genetic ablation of this receptor exacerbate arthritic scores in a collagen-induced RA mouse model and in a human RA/severe combined immunodeficiency (SCID) mouse chimera model, respectively.…”

“… 10 , 14 Interestingly, a study 14 has shown an increased expression of D2-like receptors on B cells in synovial fluids from RA patients, and administration of a D2-like receptor agonist decreased arthritic scores in mice with collagen-induced RA. 10 , 15 Moreover, both administration of D2-like receptor antagonist and genetic ablation of this receptor exacerbate arthritic scores in a collagen-induced RA mouse model and in a human RA/severe combined immunodeficiency (SCID) mouse chimera model, respectively. 10 , 16 Conversely, administration of a D1-like receptor antagonist suppressed the disease progression both in a collagen-induced RA and in a human RA/SCID mouse chimera model.…”

“… 10 , 15 Moreover, both administration of D2-like receptor antagonist and genetic ablation of this receptor exacerbate arthritic scores in a collagen-induced RA mouse model and in a human RA/severe combined immunodeficiency (SCID) mouse chimera model, respectively. 10 , 16 Conversely, administration of a D1-like receptor antagonist suppressed the disease progression both in a collagen-induced RA and in a human RA/SCID mouse chimera model. 16 , 17 …”