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

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 ␣ (TNF␣), by activated macrophages. The vagus nerve may exert antiinflammatory actions via a specific effect of its principal neurotransmitter, acetylcholine, on the ␣7 subunit of nicotinic acetylcholine receptors (␣7nAChR) 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 ␣7nAChR agonist AR-R17779.Results. Clinical arthritis was exacerbated by vagotomy and ameliorated by oral nicotine administration. Moreover, oral nicotine inhibited bone degradation and reduced TNF␣ 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 TNF␣ 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.

The α7 nicotinic acetylcholine receptor on fibroblast‐like synoviocytes and in synovial tissue from rheumatoid arthritis patients: A possible role for a key neurotransmitter in synovial inflammation

“…Still, it has been shown that electrical and pharmacologic stimulation of the vagus nerve results in decreased carrageenan-induced paw inflammation in rats (23). Consistent with these results, we recently demonstrated that manipulation of the vagus nerve has an effect on arthritis activity in the collageninduced arthritis (CIA) model of RA (24). In addition, treatment with ␣7nAChR-specific agonists reduced joint inflammation in this model.…”

“…Recently we have shown that in murine CIA, nicotine treatment as well as treatment with AR-R17779 resulted in a significant decrease in clinical signs of arthritis, joint destruction, and TNF␣ expression in the synovium and plasma (24). In the present study we show the significant decrease of IL-6 and IL-8 production by FLS after treatment with nicotine or AR-R17779; these are important proinflammatory cytokines involved in the pathogenesis of RA (37,43,44).…”

α7 Nicotinic Acetylcholine Receptor (α7nAChR) Expression in Bone Marrow-Derived Non-T Cells Is Required for the Inflammatory Reflex

“…Humoral mechanisms that restrain or inhibit these damaging responses include glucocorticoid hormones, soluble cytokine receptors, IL-10, transforming growth factor (TGF)-β and other antiinflammatory cytokines. Activation of cholinergic receptors is also known to regulate immune system activity (2)(3)(4)(5)(6)(7)(8)(9). Recent insights in protective mechanisms have revealed that neural circuits suppress release of damaging cytokines and that neural regulation of immune cell activation is an ancient mechanism dating back to nematode worms, a primitive animal with rudimentary nervous and immune systems (10)(11)(12).…”

Dopamine D2–Receptor Antagonists Ameliorate Indomethacin-Induced Small Intestinal Ulceration in Mice by Activating α7 Nicotinic Acetylcholine Receptors

“…We reported that activation of α7nAChR by nicotine and a specific α7nAChR agonist significantly attenuated indomethacin-induced small intestinal lesions (28). Similar beneficial action mediated by the activation of α7nAChR has been demonstrated in lethal sepsis (24), caeruleininduced pancreatitis (25), postoperative ileus (26), and collagen-induced arthritis (27), as well as colonic inflammation (22,23). Based on these studies and our own, we conclude that α7nAChR may be a promising target for preventing inflammatory disorders, including NSAIDinduced small intestinal ulceration.…”