Role of the cholinergic nervous system in rheumatoid arthritis: aggravation of arthritis in nicotinic acetylcholine receptor α7 subunit gene knockout mice.
BACKGROUND
The alpha7 subunit of nicotinic acetylcholine receptors (alpha7nAChR) can negatively regulate the synthesis and release of proinflammatory cytokines by macrophages and fibroblast-like synoviocytes in vitro. In addition, stimulation of the alpha7nAChR can reduce the severity of arthritis in murine collagen-induced arthritis (CIA).


OBJECTIVE
To provide more insight into the role of the alpha7nAChR in the pathogenesis of arthritis by investigating the effect of the absence of alpha7nAChR in CIA in alpha7-deficient (alpha7nAChR(-/-)) compared with wild-type (WT) mice.


METHODS
CIA was induced in alpha7nAChR(-/-) 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 alpha7nAChR(-/-) 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 alpha 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 alpha7nAChR.
van Maanen
Marjolein A
MA
Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.
Stoof
Susanne P
SP
Larosa
Gregory J
GJ
Vervoordeldonk
Margriet J
MJ
Tak
Paul P
PP
D000208:Acute Disease; D000818:Animals; D001169:Arthritis, Experimental / Q000150:complications / Q000276:immunology* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000150:complications / Q000276:immunology* / Q000473:pathology; D001851:Bone Diseases, Metabolic / Q000209:etiology / Q000276:immunology / Q000473:pathology; D002357:Cartilage Diseases / Q000209:etiology / Q000276:immunology / Q000473:pathology; D018932:Chemokine CCL2 / Q000097:blood; D018450:Disease Progression; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011978:Receptors, Nicotinic / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D064569:alpha7 Nicotinic Acetylcholine Receptor
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C579166:Chrna7 protein, mouse; D011978:Receptors, Nicotinic; D014409:Tumor Necrosis Factor-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor