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Introduction
Periodontitis is a chronic inflammatory disease characterized by the loss of periodontal attachment and alveolar bone due to bacterial infection. Neutrophils are the key immune cells involved in periodontitis (1). Gingival epithelial cells produce chemokines, such as interleukin (IL)-8 to recruit neutrophils, and periodontal pathogens stimulate dendritic cells via Toll-like receptors, resulting in the induction of the Th1/Th17 subset. Th17 cells are critical mediators of alveolar bone destruction in periodontitis, and gingival epithelial cells possess IL-17 receptor (IL-17R), to which IL-17 binds to induce IL-8 production (2-4). Although rodents lack a direct homologue of IL-8, the C-X-C motif chemokine ligand 1 (CXCL1) is regarded as a functional homologue of IL-8(5).
The main approach of current periodontal therapy is the physical excision of lesions (6). Scaling and root planing are treatments for removing plaque and calculus from the tooth surface, while periodontal surgery is debridement for excising infected granulation tissue. For deep intrabone defects, it is beneficial to use materials, such as membranes for guided tissue regeneration, enamel matrix derivatives, and fibroblast growth factor-2 (7,8). Additionally, pharmacological therapies are used as adjunctive treatments (7). Chlorhexidine and sustained-release minocycline are locally applied treatments (9,10). For systemic treatments, antibiotics are often used for short periods of time. However, few reports are available on the development of pharmacological treatments for mitigating inflammation.
We have previously demonstrated that dopamine signaling plays a crucial role in Th17 cell differentiation (11,12). There are five subtypes of dopamine receptors, D1 to D5, and these subtypes are classified into two groups: D1-like receptors and D2-like receptors. D1-like receptors, i.e., D1 and D5, induce an increase in intracellular cyclic adenosine monophosphate (cAMP), whereas D2-like receptors, i.e., D2, D3, and D4, induce a decrease in intracellular cAMP (13). In our previous studies, D1-like receptor antagonists inhibited Th17 differentiation, and attenuated neutrophilic inflammation caused by diseases in animal models, such as experimental autoimmune encephalomyelitis, autoimmune diabetes, and nephrotoxic serum nephritis models (11,14,15). It has been reported that Th17 cells markedly produced IL-8, and that the IL-8 production from activated T cells was suppressed by D2-like receptor agonists (16,17), indicating that D2-like receptor agonists can suppress neutrophilic inflammation that has already developed. Moreover, Parrado et al demonstrated that dopamine and D2-like receptor agonists upregulated...