Cholinergic Pathways, the Immune System and Arthritis
Cholinergic Pathways, the Immune System and Arthritis
It is clear that centrally acting muscarinic agonists, electrical stimulation of the vagus to activate preganglionic parasympathetic nerves, and treatment with nAChR agonists can all act systemically (though not necessarily identically) to reduce the production of inflammatory cytokines presumably mostly by macrophages. The full pathways by which they work are complex and incompletely understood. Systemic treatment with nicotinic agonists has been reported to reduce the incidence and severity of murine arthritis, although we did not confirm this finding. Sympathetic preganglionic neurons also have systemic anti-inflammatory actions that suppress the production of inflammatory cytokines. A key difference is that the sympathetic pathway is activated reflexively by peripheral inflammation while the vagal pathway appears not to be. The actions of sympathetic preganglionic neurons on arthritis may be more complex, however, and need to be clarified.
It is important that further studies are carried out in this area since clinical trials based upon the concept of the 'cholinergic anti-inflammatory pathway' have been proposed and/or are underway. At present, targeting sympathetic or adrenergic processes with drugs is less attractive because their actions may be helpful or unhelpful, depending on the disease stage. Also, the conflict between the actions of local versus systemic sympathetic nerves needs to be untangled for future progress along this line.
Much less convincing in our view is the idea that deficient control by the 'cholinergic ant-inflammatory pathway' is a significant factor leading to the onset or exacerbation of arthritis. The evidence so far indicates that there is no ongoing tone in the vagal 'cholinergic anti-inflammatory pathway' and that it is not the efferent arm of the inflammatory reflex: sympathetic pathways play that role. The loss of cardiac vagal tone in RA and other inflammatory conditions is a predictable consequence of peripheral inflammation rather than a cause. Until there is convincing evidence to the contrary, we suggest that it could mislead us if we uncritically embrace the 'cholinergic anti-inflammatory pathway' as a significant factor in the pathogenesis of RA.
Conclusion
It is clear that centrally acting muscarinic agonists, electrical stimulation of the vagus to activate preganglionic parasympathetic nerves, and treatment with nAChR agonists can all act systemically (though not necessarily identically) to reduce the production of inflammatory cytokines presumably mostly by macrophages. The full pathways by which they work are complex and incompletely understood. Systemic treatment with nicotinic agonists has been reported to reduce the incidence and severity of murine arthritis, although we did not confirm this finding. Sympathetic preganglionic neurons also have systemic anti-inflammatory actions that suppress the production of inflammatory cytokines. A key difference is that the sympathetic pathway is activated reflexively by peripheral inflammation while the vagal pathway appears not to be. The actions of sympathetic preganglionic neurons on arthritis may be more complex, however, and need to be clarified.
It is important that further studies are carried out in this area since clinical trials based upon the concept of the 'cholinergic anti-inflammatory pathway' have been proposed and/or are underway. At present, targeting sympathetic or adrenergic processes with drugs is less attractive because their actions may be helpful or unhelpful, depending on the disease stage. Also, the conflict between the actions of local versus systemic sympathetic nerves needs to be untangled for future progress along this line.
Much less convincing in our view is the idea that deficient control by the 'cholinergic ant-inflammatory pathway' is a significant factor leading to the onset or exacerbation of arthritis. The evidence so far indicates that there is no ongoing tone in the vagal 'cholinergic anti-inflammatory pathway' and that it is not the efferent arm of the inflammatory reflex: sympathetic pathways play that role. The loss of cardiac vagal tone in RA and other inflammatory conditions is a predictable consequence of peripheral inflammation rather than a cause. Until there is convincing evidence to the contrary, we suggest that it could mislead us if we uncritically embrace the 'cholinergic anti-inflammatory pathway' as a significant factor in the pathogenesis of RA.
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