The cholinergic anti-inflammatory pathway: A critical review
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.
References (37)
- et al.
Vagal control of lymphocyte release from rat thymus
J. Auton. Nerv. Syst.
(1994) - et al.
Acetylcholinesterase staining and choline acetyltransferase activity in the young adult rat spleen: lack of evidence for cholinergic innervation
Brain. Behav. Immun.
(1993) - et al.
Characterization of vagal innervation to the rat celiac, suprarenal and mesenteric ganglia
J. Auton. Nerv. Syst.
(1993) - et al.
Role of vagus nerve signaling in CNI-1493-mediated suppression of acute inflammation
Auton. Neurosci.
(2000) - et al.
Anesthesia-specific protection from endotoxic shock is not mediated through the vagus nerve
Surgery
(2005) - et al.
Autonomic innervation and regulation of the immune system (1987–2007)
Brain Behav. Immun.
(2007) The spleen in lymphocyte migration
Immunol. Today
(1988)- et al.
Neural reflexes in inflammation and immunity
J. Exp. Med.
(2012) - et al.
Reflex principles of immunological homeostasis
Annu. Rev. Immunol.
(2012) - et al.
Pharmacological stimulation of the cholinergic antiinflammatory pathway
J. Exp. Med.
(2002)