Abstract

BackgroundThe cholinergic anti-inflammatory pathway (CAP) has a strong anti-inflammatory effect on collagen-induced arthritis (CIA), a classic animal model of rheumatoid arthritis (RA). However, the underlying immune regulatory mechanism remains unclear. Here, we investigated the effect of the CAP on arthritis development and the involvement of dendritic cells (DCs).MethodsForty DBA/1 mice were randomly divided into five groups: a control group (sham vagotomy+ phosphate-buffered saline; shamVGX+PBS), a CIA group (shamVGX+CIA + PBS), a vagotomy group (VGX + CIA + PBS), a GTS-21 (4 mg/kg) group (shamVGX+CIA + GTS-4), and a GTS-21 (8 mg/kg) group (shamVGX+CIA + GTS-8). The vagotomy group underwent left cervical vagotomy 4 days before arthritis induction, whereas the sham-vagotomy group underwent vagus nerve exposure. Mice were pretreated with GTS-21 by intraperitoneal injection on the day of surgery. The degree of arthritis was measured by using the arthritis score, hematoxylin and eosin staining, and TRAP (tartrate-resistant acid phosphatase) staining. Flow cytometry was used to detect the expression of CD80 and major histocompatibility complex II (MHC II) on CD11c+ DCs in the spleen. Luminex was used to detect the serum concentration of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFα), and IL-10. Immunohistochemistry was used to detect CD11c expression in the synovium. The effects of GTS-21 on DC differentiation and maturation were examined in vitro by treating bone marrow–derived DCs with GTS-21 and assessing differentiation and maturation. Flow cytometry was used to analyze CD80 and MHC II expression on the surface of DCs.ResultsGTS-21 treatment ameliorated clinical arthritis in a mouse model of CIA in vivo, decreasing the secretion of pro-inflammatory cytokines in the serum and downregulating CD80 and MHC II expression on DCs in the spleen of CIA mice. GTS-21 treatment strongly suppressed the infiltration of DCs into the synovium. Vagotomy itself did not exacerbate the severity of arthritis in CIA mice. In vitro, GTS-21 (10 μmol/L) significantly downregulated CD80 and MHC II in bone marrow–derived immature DCs and this effect was blocked by the α7-nicotinic acetylcholine receptor antagonist methyllycaconitine (MLA). However, GTS-21 had no effects on mature DCs.ConclusionsThe present study provides new insight into the mechanism underlying the effects of the CAP on RA and indicates that the immunosuppressive effect of GTS-21 may be mediated by the inhibition of DC differentiation.

Highlights

  • Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and cartilage and bone destruction

  • GTS-21 attenuates the inflammatory response in collageninduced arthritis (CIA) mice To determine whether the cholinergic anti-inflammatory pathway (CAP) regulates the inflammatory response in rheumatoid arthritis (RA), the left vagus nerve was sectioned to inhibit the pathway, and GTS-21 was injected into the peritoneal cavity to activate the pathway 4 days before CIA induction

  • The ameliorating effect of GTS-21 on CIA was confirmed by hematoxylin and eosin (HE) staining and tartrate-resistant acid phosphatase (TRAP) staining of joints

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Summary

Introduction

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and cartilage and bone destruction. Mature DCs in the synovium and secondary lymphoid organs can present antigens to naïve T cells and induce T-cell activation [2, 3]; DCs secrete inflammatory cytokines such as interleukin-12 (IL-12), IL-23, IL-6, tumor necrosis factor-alpha (TNF-α), and IL-1 to induce Th1, Th2, and Th17 differentiation, aggravating the inflammation of the synovium [4,5,6,7]. Clinical trials confirmed that the strategy is safe, feasible, and acceptable [13, 14]. These data suggest that DCs are a promising target for the treatment of RA. We investigated the effect of the CAP on arthritis development and the involvement of dendritic cells (DCs)

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