Article Text

PDF
Extended report
Role of the cholinergic nervous system in rheumatoid arthritis: aggravation of arthritis in nicotinic acetylcholine receptor α7 subunit gene knockout mice
  1. Marjolein A van Maanen1,
  2. Susanne P Stoof1,2,
  3. Gregory J LaRosa3,4,
  4. Margriet J Vervoordeldonk1,2,
  5. Paul P Tak1
  1. 1Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands
  2. 2Academic Medical Center/University of Amsterdam, Arthrogen BV, Amsterdam, The Netherlands
  3. 3Cornerstone Therapeutics Inc, Cary, North Carolina, USA
  4. 4Bikam Pharmaceuticals, Cambridge, Massachusetts, USA
  1. Correspondence to Dr P P Tak, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, F4-105, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; p.p.tak{at}amc.uva.nl

Abstract

Background The α7 subunit of nicotinic acetylcholine receptors (α7nAChR) can negatively regulate the synthesis and release of proinflammatory cytokines by macrophages and fibroblast-like synoviocytes in vitro. In addition, stimulation of the α7nAChR can reduce the severity of arthritis in murine collagen-induced arthritis (CIA).

Objective To provide more insight into the role of the α7nAChR in the pathogenesis of arthritis by investigating the effect of the absence of α7nAChR in CIA in α7-deficient (α7nAChR-/-) compared with wild-type (WT) mice.

Methods CIA was induced in α7nAChR-/- and WT littermate mice at day 0 by immunisation with chicken collagen type II (cCII) followed by a booster injection with cCII on day 20. Mice were killed on day 44 or day 63 and arthritis activity as well as radiological and histological damage were scored. The effects on the immune response were evaluated by measurement of antigen-specific antibodies and cytokines, and evaluation of the effects on antigen-specific stimulated spleen cells.

Results In α7nAChR-/- mice a significant increase in the incidence and severity of arthritis as well as increased synovial inflammation and joint destruction were seen. Exacerbation of CIA was associated with elevated systemic proinflammatory cytokines and enhanced T-helper cell 1 (Th1)-cytokine and tumour necrosis factor α production by spleen cells. Moreover, a specific decrease in the collagen-specific ‘Th1-associated’ IgG2a response was seen, whereas IgG1 titres were unaffected.

Conclusions The results presented here indicate that immune cell function in a model of rheumatoid arthritis is regulated by the cholinergic system and, at least in part, mediated by the α7nAChR.

Statistics from Altmetric.com

Footnotes

  • MJV and PPT contributed equally to this work

  • Competing interests GJL owns stock options of Critical Therapeutics.

  • Provenance and peer review Not commissioned; externally peer reviewed.

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.