The immunomodulatory effect of the autonomic nervous system has raised considerable interest over the last decades. Studying the influence on the immune system and the role in inflammation of the sympathetic as well as the parasympathetic nervous system not only will increase our understanding of the mechanism of disease, but also could lead to the identification of potential new therapeutic targets for chronic immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA). An imbalanced autonomic nervous system, with a reduced parasympathetic and increased sympathetic tone, has been a consistent finding in RA patients. Studies in animal models of arthritis have shown that influencing the sympathetic (via α-and β-adrenergic receptors) and the parasympathetic (via the nicotinic acetylcholine receptor α7nAChR or by electrically stimulating the vagus nerve) nervous system can have a beneficial effect on inflammation markers and arthritis. The immunosuppressive effect of the parasympathetic nervous system appears less ambiguous than the immunomodulatory effect of the sympathetic nervous system, where activation can lead to increased or decreased inflammation depending on timing, doses and kind of adrenergic agent used. In this review we will discuss the current knowledge of the role of both the sympathetic (SNS) and parasympathetic nervous system (PNS) in inflammation with a special focus on the role in RA. In addition, potential antirheumatic strategies that could be developed by targeting these autonomic pathways are discussed.
Role of the cholinergic nervous system in rheumatoid arthritis: aggravation of arthritis in nicotinic acetylcholine receptor alpha7 subunit gene knockout mice van Maanen, M.A.; Stoof, S.P.; Larosa, G.J.; Vervoordeldonk, M.J.; Tak, P.P. General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. 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-defi cient (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 antigenspecifi c antibodies and cytokines, and evaluation of the effects on antigen-specifi c stimulated spleen cells.Results In α7nAChR -/-mice a signifi cant increase in the incidence and severity of arthritis as well as increased synovial infl ammation and joint destruction were seen. Exacerbation of CIA was associated with elevated systemic proinfl ammatory cytokines and enhanced T-helper cell 1 (Th1)-cytokine and tumour necrosis factor α production by spleen cells. Moreover, a specifi c decrease in the collagen-specifi c '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.
Objective. Recent studies have suggested an important role for neurotransmitters as modulators of inflammation. Therefore, we undertook this study to investigate the expression of the ␣7 subunit of the nicotinic acetylcholine receptor (␣7nAChR) and its function in rheumatoid arthritis (RA).Methods. The potential role of the ␣7nAChR in modulating proinflammatory cytokine expression in fibroblast-like synoviocytes (FLS) was identified by screening an adenoviral short hairpin RNA (Ad.shRNA) library. An ␣7-specific antibody was used for immunohistochemistry, and fluorescein isothiocyanate-labeled ␣-bungarotoxin, which binds specifically to the ␣7nAChR, was used for immunofluorescence. Gene expression in FLS was determined by quantitative polymerase chain reaction with primers specific for the ␣7nAChR. In addition, we analyzed messenger RNA (mRNA) expression of dup␣7, a variant ␣7 transcript. Next, we studied the functional role of the ␣7nAChR in RA FLS by examining the effects of ␣7-specific agonists on the production of interleukin-6 (IL-6) and IL-8 by activated FLS.Results. A screen using an Ad.shRNA library against 807 transcripts revealed that a specific ␣7nAChR shRNA potently modulated IL-8 and matrix metalloproteinase expression in FLS. The ␣7nAChR was expressed in the inflamed synovium from RA patients, predominantly in the intimal lining layer. We found ␣7nAChR expression at both the mRNA and protein level in cultured RA FLS. FLS also constitutively expressed dup␣7 mRNA. Specific ␣7nAChR agonists reduced tumor necrosis factor ␣-induced IL-6 and IL-8 production by FLS.
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