Abstract
Acetylcholine, the principal vagus neurotransmitter, inhibits inflammation by suppressing the production of pro-inflammatory cytokines through a mechanism dependent on the α7 nicotinic acetylcholine receptor subunit (alpha7nAChR) that explains why vagus nerve stimulation is anti-inflammatory in nature. Strong expression of alpha7nAChR in the synovium of rheumatoid arthritis and psoriatic arthritis patients was detected. Peripheral macrophages and synovial fibroblasts respond in vitro to specific alpha7nAChR cholinergic stimulation with potent inhibition of proinflammatory cytokines. Fibroblasts balance inflammatory mechanisms and arthritis development through feedback cholinergic stimulation by nearby immune cells. Collagen induced arthritis in alpha7nAChR(-/-) mice was significantly severe and showed increased synovial inflammation and joint destruction compared to the wild-type mice. Similar to vagal nerve stimulation and alpha7nAChR agonists, polyunsaturated fatty acids: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) also suppress inflammation. In view of their similar anti-inflammatory actions, it is proposed that vagal nerve stimulation, alpha7nAChR agonists and EPA and DHA may augment the formation of anti-inflammatory lipid molecules: lipoxins, resolvins, protectins and maresins. This implies that therapies directed at regulation of the cholinergic and alpha7nAChR mediated mechanisms and enhancing the formation of lipoxins, resolvins, protectins and maresins may halt and/or ameliorate rheumatoid arthritis, lupus and other rheumatological conditions.
Highlights
Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease of unknown cause, characterized by chronic synovial inflammation and progressive erosions of cartilage and bone due to the release of excess cytokines that stimulate the inflammatory reaction
Inflammation is at the core of the autoimmune diseases that seem to arise through aberrant reactions of the human adaptive or innate immune systems due to the activation of the patient’s immune system against the body’s own proteins
The proposal that vagal tone is decreased, sympathetic tone is enhanced and increased production of IL-6, tumor necrosis factor-a (TNF-a), migration inhibitory factor (MIF) and high mobility group box 1 (HMGB1) and decrease in plasma and tissue concentrations of arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and their products lipoxins, resolvins, protectins and maresins occurs in RA and lupus has important therapeutic implications
Summary
Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease of unknown cause, characterized by chronic synovial inflammation and progressive erosions of cartilage and bone due to the release of excess cytokines that stimulate the inflammatory reaction. Such an interaction between acetylcholine and PUFAs may explain their anti-inflammatory nature and possible beneficial action of VNS in inflammatory conditions such as RA and lupus [17,18,19,20,21,22,36,37,38,39,40] Hypothesis It is evident from the preceding discussion that vagus nerve stimulation suppresses inflammation, alpha7nAChR agonists have the ability to ameliorate rheumatoid arthritis, especially in animal models of arthritis whereas arthritis could be exacerbated by vagotomy and suppressed by oral nicotine administration; oral nicotine and/or alpha7nAChR agonists inhibit bone degradation and reduced TNF-a expression in synovial tissue and reduced synovial inflammation (see Figure 1). In experimental animals and humans the ability of VNS to augment the formation of lipoxins, resolvins, maresins and protectins in various tissues and enhance their levels in the plasma could be assessed
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