Elsevier

Autonomic Neuroscience

Volume 182, May 2014, Pages 65-69
Autonomic Neuroscience

The cholinergic anti-inflammatory pathway: A critical review

https://doi.org/10.1016/j.autneu.2013.12.007Get rights and content

Abstract

From a critical review of the evidence on the cholinergic anti-inflammatory pathway and its mode of action, the following conclusions were reached.

(1) Both local and systemic inflammation may be suppressed by electrical stimulation of the peripheral cut end of either vagus.

(2) The spleen mediates most of the systemic inflammatory response (measured by TNF-α production) to systemic endotoxin and is also the site where that response is suppressed by vagal stimulation.

(3) The anti-inflammatory effect of vagal stimulation depends on the presence of noradrenaline-containing nerve terminals in the spleen.

(4) There is no disynaptic connection from the vagus to the spleen via the splenic sympathetic nerve: vagal stimulation does not drive action potentials in the splenic nerve.

(5) Acetylcholine-synthesizing T lymphocytes provide an essential non-neural link in the anti-inflammatory pathway from vagus to spleen.

(6) Alpha-7 subunit-containing nicotinic receptors are essential for the vagal anti-inflammatory action: their critical location is uncertain, but is suggested here to be on splenic sympathetic nerve terminals.

(7) The vagal anti-inflammatory pathway can be activated electrically or pharmacologically, but it is not the efferent arm of the inflammatory reflex response to endotoxemia.

Section snippets

Historical origins

The concept of the cholinergic anti-inflammatory pathway dates back to investigations on the anti-inflammatory actions of a drug (CNI-1493). This agent was shown to suppress the inflammatory response in the rat's paw after local injection of the irritant, carageenin (Borovikova et al., 2000a). The anti-inflammatory action of the drug was found to be indirect, via the brain, because it was effective at far lower intracerebroventricular (ICV) doses compared with those given systemically. Its

Developments: involvement of the spleen and the splenic nerves

In 2006, the spleen was demonstrated to be essential for the inhibition of systemic inflammation by vagal stimulation (Huston et al., 2006, Huston et al., 2008). However, these workers also found that removing the spleen itself lowered the production and plasma levels of inflammatory cytokines to the same degree as did vagal stimulation when the spleen was intact. The spleen thus plays a dual role: (1) it is responsible for most of the production of inflammatory cytokines in response to

A spanner in the works: no disynaptic pathway from vagus to spleen

The central role of the spleen in the systemic inflammatory response is clear, as is the finding that its sympathetic innervation is necessary for the anti-inflammatory response to vagal stimulation. We recently tested the idea that there is a disynaptic link from the vagus to the splenic nerve (Bratton et al., 2012). Anatomically, we found that the large majority of splenic-projecting sympathetic neurons were located in the suprarenal rather than the celiac ganglia and that vagal efferent

Resolution

How can these apparently contradictory findings be reconciled? The splenic nerves are essential for the vagal action on inflammation, yet that role is not played by relaying action potentials from vagus to spleen. Fortunately, some clues in the literature suggest a relevant mechanism. In another inflammatory model, Miao et al. (1996) found that synovial plasma extravasation in response to bradykinin depended critically on the presence of sympathetic nerve terminals, but not on their action

Recent developments

In 2011, Rosas-Ballina and colleagues found that the acetylcholine necessary for the “cholinergic anti-inflammatory pathway,” activated by vagal stimulation, was not neural in origin. In a series of elegant experiments, these workers found that a subset of T lymphocytes synthesized acetylcholine, and these are present in the spleens of mice (Rosas-Ballina et al., 2011) (Gautron et al., 2013). Without these T-cells (in nude mice, who lack functional T-cells), vagal stimulation had no

Vagal communication to the spleen—the non-neural link

The evidence above makes any direct neural link from the vagus to the spleen highly unlikely, so we now need to consider non-neural channels of communication. The mechanism is presently unknown, but cellular migration is an attractive possibility. Lymphocytes circulate, and the spleen sequesters a proportion of these circulating cells (Pabst, 1988). Its ability to do so is enhanced during systemic inflammation (Rogausch et al., 2003). The vagus, although it does not innervate the spleen,

Summary of salient evidence on the cholinergic anti-inflammatory pathway in vivo

  • 1)

    CNI-1493 acts via the brain to inhibit local and systemic inflammation. The action on local inflammation is prevented by cutting the vagi.

  • 2)

    Muscarinic agonists when applied ICV also suppress systemic inflammation. Cutting the vagi blocks this effect, but a peripherally acting muscarinic antagonist, atropine methyl nitrate, does not.

These findings show that the vagus is an essential efferent pathway for the central actions of these drugs to suppress inflammation.

  • 3)

    Electrical stimulation of the

The inflammatory reflex

The term “inflammatory reflex” was introduced a decade ago by Tracey in an influential review (Tracey, 2002). It describes a limiting action of the central nervous system (CNS) on inflammation: CNS pathways respond to signals of injury or inflammation and act reflexly to suppress the inflammatory cascade. That anti-inflammatory action may be on local and/or on systemic inflammation. Most of the evidence has been gathered with respect to systemic inflammation—typically that produced by giving

Acknowledgements

We wish to acknowledge support by project grants 628655 and 1051102 from the National Health and Medical Research Council (NHMRC) of Australia and from the Victorian Government Operational Infrastructure Support Program. DM was supported by the Fondazione Cassa di Risparmio Bologna. RMcA was supported by Principal Research Fellowship 566667 from NHMRC.

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