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, 17 (1), 87

The Interface Between Cholinergic Pathways and the Immune System and Its Relevance to Arthritis


The Interface Between Cholinergic Pathways and the Immune System and Its Relevance to Arthritis

Robin M McAllen et al. Arthritis Res Ther.


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.


Figure 1
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.
Figure 2
Figure 2
Nicotine and AR-R17779 fail to ameliorate collagen-induced arthritis (CIA). Male DBA/1 mice (6 to 8 weeks) were immunized for CIA on day 0 (100 μg chick type II collagen in complete Freund’s adjuvant containing 5 mg/ml of heat-killed Mycobacterium tuberculosis), followed by a booster injection on day 21 [85]. Beginning on day 21, mice were treated intraperitoneally with nicotine (400 μg/kg), AR-R17779 (5 mg/kg) or vehicle (saline), twice daily for 7 days. (A) Cumulative incidence (percentage). (B) Change in paw thickness (calliper). (C) Clinical score (0 to 4 per paw; maximum score of 16 per mouse). Data are expressed as mean ± standard error of the mean; n = 8 mice per group.

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