Cholinergic Pathways, the Immune System and Arthritis
Cholinergic Pathways, the Immune System and Arthritis
The nervous and immune systems are likely to be interacting in arthritis, with the possible involvement of both neural and non-neural cholinergic transmission. Centrally acting muscarinic agonists, electrical stimulation of the vagus and treatment with nicotinic receptor agonists can all act systemically to reduce inflammation, although the responsible pathways are incompletely understood. While this 'cholinergic anti-inflammatory pathway' is widely viewed as a significant pathophysiological mechanism controlling inflammation, the evidence supporting this view is critically reviewed and considered inconclusive; an alternative pathway via sympathetic nerves is implicated. This review also discusses how cholinergic pathways, both neural and non-neural, may impact on inflammation and specifically arthritis. Nicotinic agonists have been reported to reduce the incidence and severity of murine arthritis, albeit an observation we could not confirm, and clinical studies in rheumatoid arthritis have been proposed and/or are underway. While the therapeutic potential of nicotinic agonists and vagal stimulation is clear, we suggest that the 'cholinergic anti-inflammatory pathway' should not be uncritically embraced as a significant factor in the pathogenesis of rheumatoid arthritis.
Nervous and immune system interactions are likely to be occurring in arthritis, as exemplified by the observation that hemiplegic patients do not develop psoriatic arthritis on their denervated side. In this review we will try to identify relevant cholinergic pathways in the physiological and pathophysiological sense - those that are actually used by the body in vivo. Recently it has become increasingly apparent that, as well as responding to transmitters released by autonomic nerves, cells of the immune system may express and intercommunicate by these same transmitters. The different types of cholinergic pathway are shown in Figure 1. These are (i) central nervous, (ii) preganglionic and postganglionic parasympathetic, (iii) preganglionic and postganglionic sympathetic, (iv) somatic motoneuron and (v) non-neural (cell-cell interaction). All somatic motoneurons, all preganglionic neurons and most postganglionic parasympathetic neurons are cholinergic. Only a minority of central and sympathetic postganglionic neurons are cholinergic. The latter supply targets such as the sweat glands and are unlikely to be directly involved in modulating immune function. Vagal afferent neurons are not included since they are generally not cholinergic.
(Enlarge Image)
Figure 1.
Schematic summary of the types of cholinergic pathway. The following cholinergic pathways are highlighted in green in successive diagrams: (i) central nervous, (ii) preganglionic and postganglionic parasympathetic (cranial and sacral), (iii) preganglionic and postganglionic sympathetic, (iv) somatic motoneuron and (v) non-neural (showing an example of a cholinergic cell-cell interaction). All somatic motoneurons, all sympathetic and parasympathetic preganglionic neurons and most parasympathetic postganglionic neurons are cholinergic; the remainder are subsets. ChAT = choline acetyl transferase-positive; that is, acetylcholine (ACh) expressing.
The cholinergic neurons that influence immune function may do so directly by the actions of synaptically released acetylcholine on immune cells, or indirectly by synaptically exciting other neurons with the same or different transmitters (for example, noradrenaline). They do not directly innervate joints. The immune mechanisms to be considered will focus on the control of inflammation and, where specific information exists, its relevance to arthritis. We will then review the pharmacological actions of cholinergic agonists on monocytes/macrophages and report new findings on how they affect murine collagen-induced arthritis.
Abstract and Introduction
Abstract
The nervous and immune systems are likely to be interacting in arthritis, with the possible involvement of both neural and non-neural cholinergic transmission. Centrally acting muscarinic agonists, electrical stimulation of the vagus and treatment with nicotinic receptor agonists can all act systemically to reduce inflammation, although the responsible pathways are incompletely understood. While this 'cholinergic anti-inflammatory pathway' is widely viewed as a significant pathophysiological mechanism controlling inflammation, the evidence supporting this view is critically reviewed and considered inconclusive; an alternative pathway via sympathetic nerves is implicated. This review also discusses how cholinergic pathways, both neural and non-neural, may impact on inflammation and specifically arthritis. Nicotinic agonists have been reported to reduce the incidence and severity of murine arthritis, albeit an observation we could not confirm, and clinical studies in rheumatoid arthritis have been proposed and/or are underway. While the therapeutic potential of nicotinic agonists and vagal stimulation is clear, we suggest that the 'cholinergic anti-inflammatory pathway' should not be uncritically embraced as a significant factor in the pathogenesis of rheumatoid arthritis.
Introduction
Nervous and immune system interactions are likely to be occurring in arthritis, as exemplified by the observation that hemiplegic patients do not develop psoriatic arthritis on their denervated side. In this review we will try to identify relevant cholinergic pathways in the physiological and pathophysiological sense - those that are actually used by the body in vivo. Recently it has become increasingly apparent that, as well as responding to transmitters released by autonomic nerves, cells of the immune system may express and intercommunicate by these same transmitters. The different types of cholinergic pathway are shown in Figure 1. These are (i) central nervous, (ii) preganglionic and postganglionic parasympathetic, (iii) preganglionic and postganglionic sympathetic, (iv) somatic motoneuron and (v) non-neural (cell-cell interaction). All somatic motoneurons, all preganglionic neurons and most postganglionic parasympathetic neurons are cholinergic. Only a minority of central and sympathetic postganglionic neurons are cholinergic. The latter supply targets such as the sweat glands and are unlikely to be directly involved in modulating immune function. Vagal afferent neurons are not included since they are generally not cholinergic.
(Enlarge Image)
Figure 1.
Schematic summary of the types of cholinergic pathway. The following cholinergic pathways are highlighted in green in successive diagrams: (i) central nervous, (ii) preganglionic and postganglionic parasympathetic (cranial and sacral), (iii) preganglionic and postganglionic sympathetic, (iv) somatic motoneuron and (v) non-neural (showing an example of a cholinergic cell-cell interaction). All somatic motoneurons, all sympathetic and parasympathetic preganglionic neurons and most parasympathetic postganglionic neurons are cholinergic; the remainder are subsets. ChAT = choline acetyl transferase-positive; that is, acetylcholine (ACh) expressing.
The cholinergic neurons that influence immune function may do so directly by the actions of synaptically released acetylcholine on immune cells, or indirectly by synaptically exciting other neurons with the same or different transmitters (for example, noradrenaline). They do not directly innervate joints. The immune mechanisms to be considered will focus on the control of inflammation and, where specific information exists, its relevance to arthritis. We will then review the pharmacological actions of cholinergic agonists on monocytes/macrophages and report new findings on how they affect murine collagen-induced arthritis.
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