Norepinephrine Inhibits Th17 Cells via β2-Adrenergic Receptor (β2-AR) Signaling in a Mouse Model of Rheumatoid Arthritis

Background: Norepinephrine (NE), a neurotransmitter released from the sympathetic nerves, has been shown to be involved in rheumatoid arthritis (RA). However, its role in the sympathetic nervous system in RA is divergent. Herein, we demonstrate that the sympathetic neurotransmitter NE exerts an anti-inflammatory effect in collagen-induced arthritis (CIA), a mouse model of RA, by inhibiting Th17 cell differentiation and function via beta 2-adrenergic receptor (beta 2-AR) signaling. Material/Methods: CIA was prepared by intradermal injection of collagen type II in the tail base of DBA1/J mice. On the 41st day post-immunization, the mice were used as CIA models. CD4(+) T cells from the spleen were purified using magnetic cell sorting and activated with anti-CD3 anti-CD28 antibodies. Th17 cells were polarized from the CD4(+) T cells using various antibodies and cytokines. Results: Co-expression of CD4 and beta 2-AR was observed in spleens of both intact and CIA mice. The beta 2-AR expression in the ankle and spleen was downregulated in CIA mice. CIA induced increases in production of interleukin (IL)-17 and IL-22, CD25-IL-17(+) cell percentage, and ROR-gamma t expression in CD4(+) T cells. Importantly, NE reduced the CIA-induced CD4(+) T cell shift towards Th17 phenotype, and the beta 2-AR antagonist ICI118551 blocked the NE effect. Moreover, the beta 2-AR agonist terbutaline (Terb) inhibited CIA-induced CD4(+) T cell proliferation and shift towards Th17 phenotype, and the protein kinase A (PKA) inhibitor H-89 abolished the agonist effect. Terb also reduced CIA-induced Th17 enhancement, and H-89 impaired the Terb effect. Conclusions: NE inhibits Th17 cell differentiation and function in CIA condition by activation of beta 2-AR/PKA signaling.