Stimulation of nicotinic acetylcholine receptors attenuates collagen-induced arthritis in mice

Authors

  • Marjolein A. van Maanen,

    1. Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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  • Maria C. Lebre,

    1. Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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  • Tom van der Poll,

    1. Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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  • Gregory J. LaRosa,

    1. Critical Therapeutics, Inc., Lexington, Massachusetts
    Current affiliation:
    1. Bikam Pharmaceuticals, Cambridge, MA
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    • Dr. LaRosa owns stock or stock options in Critical Therapeutics, Inc.

  • Daniel Elbaum,

    1. Critical Therapeutics, Inc., Lexington, Massachusetts
    Current affiliation:
    1. FoldRx Pharmaceuticals, Cambridge, MA
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  • Margriet J. Vervoordeldonk,

    1. Academic Medical Center, University of Amsterdam and Arthrogen BV, Amsterdam, The Netherlands
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    • Drs. Vervoordeldonk and Tak contributed equally to this work.

  • Paul P. Tak

    Corresponding author
    1. Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
    • Division of Clinical Immunology and Rheumatology, F4-218, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
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    • Drs. Vervoordeldonk and Tak contributed equally to this work.


Abstract

Objective

The parasympathetic nervous system, through the vagus nerve, can down-regulate inflammation in vivo by decreasing the release of cytokines, including tumor necrosis factor α (TNFα), by activated macrophages. The vagus nerve may exert antiinflammatory actions via a specific effect of its principal neurotransmitter, acetylcholine, on the α7 subunit of nicotinic acetylcholine receptors (α7nAChR) on macrophages. The present study was undertaken to obtain insight into the role of the cholinergic antiinflammatory pathway in arthritis.

Methods

To inhibit the cholinergic antiinflammatory pathway, mice were subjected to unilateral cervical vagotomy or sham surgery, after which arthritis was induced with type II collagen. In a separate study, nicotine was added to the drinking water of mice with collagen-induced arthritis (CIA). In addition, we investigated the effects of intraperitoneally (IP)–injected nicotine and the specific α7nAChR agonist AR-R17779.

Results

Clinical arthritis was exacerbated by vagotomy and ameliorated by oral nicotine administration. Moreover, oral nicotine inhibited bone degradation and reduced TNFα expression in synovial tissue. Both IP-injected nicotine and AR-R17779 ameliorated clinical arthritis and reduced synovial inflammation. This was accompanied by a reduction of TNFα levels in both plasma and synovial tissue. The effect of AR-R17779 was more potent compared with that of nicotine and was associated with delayed onset of the disease as well as with protection against joint destruction.

Conclusion

These data provide the first evidence of a role of the cholinergic antiinflammatory pathway in the murine CIA model of rheumatoid arthritis.

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