1

AUTONOMIC NEUROSCIENCE: IN PRESS (Accepted 7/8/2013)

The cholinergic anti-inflammatory pathway: a critical review

D.Martelli1,4, M.J. McKinley1,2 and R.M. McAllen1,3

1
Florey Institute of Neuroscience and Mental Health,
2
Department of Physiology and 3Department of Anatomy & Neuroscience, University of
Melbourne, Parkville 3010, Australia
and
4
Dept. of Biomedical and Neuromotor Sciences, Physiology Division, University of
Bologna, Italy.

Corresponding Author:
Robin McAllen
Florey Institute of Neuroscience and Mental Health
University of Melbourne
Parkville, 3010
Australia.
Email: rmca@florey.edu.au
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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
antiinflammatory pathway from vagus to spleen.
6) Alpha-7 subunit-containing nicotinic receptors are essential for the vagal
antiinflammatory action: their critical location is uncertain, but is suggested here to be on
splenic sympathetic nerve terminals.
7) The vagal antiinflammatory pathway can be activated electrically or
pharmacologically, but it is not the efferent arm of the inflammatory reflex response to
endotoxaemia.
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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 . 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 anti-inflammatory action was prevented by
cutting the vagi. Strikingly, the anti inflammatory action of the drug could be mimicked
by electrical stimulation of the vagi . Next, the anti-inflammatory actions of CNI-1493
and of electrical stimulation of the vagus were tested in the context of systemic
inflammation, produced by high doses of intravenous lipopolysaccharide (LPS) . The
inflammatory response was most commonly assessed by measurements of tumour
necrosis factor alpha (TNFα), a necessary and sufficient mediator of inflammation . Most
subsequent evidence on the cholinergic antiinflammatory pathway comes from studies
using this paradigm, and that evidence will be the focus of the present critical review.
Borovikova and colleagues demonstrated that either giving CNI-1493 or
stimulating the peripheral end of either vagus was effective in lessening the systemic
inflammatory response in rats injected with high doses of intravenous LPS derived from
E.coli (15 mg/kg, the LD50) . Both stimuli were found to suppress the production of
inflammatory cytokines such as TNFα in liver and spleen, and to reduce their circulating
levels . Here, too, the action of CNI-1493 was prevented by cutting the vagi. Although
the anti-inflammatory action of CNI-1493 could be blocked by atropine , later
experiments showed that the effect of vagal stimulation could not be blocked by a
muscarinic antagonist (atropine methyl nitrate) . These findings were interpreted as
showing a central but not a peripheral muscarinic link in the vagal anti-inflammatory
pathway and, indeed, centrally acting muscarinic agonists were shown to suppress
inflammation in a manner that depended on the integrity of the vagi . Interestingly, an
alternative explanation was not investigated: that electrical stimulation of the peripheral
end of the cut vagus might act by a mechanism distinct from that caused by CNI-1493 or
central muscarinic agonists. Electrical stimulation would have activated not only
preganglionic efferent fibres but also antidromically driven vagal afferent fibres (over
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80% of the vagus is afferent), perhaps explaining why the peripheral action is not blocked
by muscarinic antagonists.
An essential nicotinic link in the peripheral pathway was then demonstrated by
the finding that while the anti-inflammatory action of vagal stimulation works in wild-
type mice, it does not work in mice that lack the α7 nicotinic receptor subunit . Wang and
colleagues inferred that the critical nicotinic receptor was on macrophages, because in
vitro studies found that nicotinic agonists suppressed the TNFα production by
macrophages of wild-type mice but not those from α7 knockout mice.
Because of the involvement of the vagus and cholinergic receptors, these
mechanisms were termed the ‘Cholinergic antiinflammatory pathway’ .

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 . 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 intravenous LPS, and 2) it is the site where that production is suppressed by
vagal stimulation.
The initial formulation of the cholinergic anti-inflammatory pathway postulated
that the action of vagal efferent neurons was exerted directly on macrophages (Fig 1 A, ).
The discovery of the central importance of the spleen necessitated a modification of this
plan, because of evidence that the rodent spleen receives little or no direct (cholinergic)
innervation from the vagus, only noradrenergic fibres from the splenic sympathetic
nerves . While not all workers agree on this point , a recent study using an efficient
transgenic label for cholinergic structures in mice confirmed that cholinergic innervation
of the spleen was sparse .
To account for the vagal signal reaching the spleen, a disynaptic connection was
postulated . Preganglionic parasympathetic fibres in the vagus were proposed to synapse
with postganglionic sympathetic neurons in the celiac ganglion: those postganglionic
sympathetic neurons were then proposed to travel in the splenic nerves to innervate the
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spleen (Fig 1 B). This postulated disynaptic pathway has been presented in numerous
review articles from several sources . Evidence used in support of this model includes the
finding that some vagal preganglionic neurons innervate the celiac ganglion, a
sympathetic ganglion , from which postganglionic sympathetic neurons could emerge to
form the splenic nerves and innervate the spleen. Further support was taken from the
finding that the splenic sympathetic nerves are necessary for the anti-inflammatory action
of vagal stimulation . The vagal antiinflammatory action was not present in animals
whose spleens were surgically denervated a week before the test, so that its sympathetic
innervation had degenerated. Depletion of noradrenaline by reserpine treatment also
prevented the anti-inflammatory action of vagal stimulation .
It may be noted that this model substitutes adrenergic for cholinergic signalling to
macrophages as the final link that suppresses their production of TNFα. Splenic
macrophages express both nicotinic and beta adrenergic receptors, however, and both
have been shown in vitro to suppress TNFα production .

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 . 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 terminals made no synaptic contact with them.
Functionally, we showed that electrical stimuli delivered to the peripheral end of the cut
vagus, using the same parameters that were previously shown to inhibit inflammation,
did not drive action potentials in the splenic nerve . Together, these findings make it clear
that the model showing a disynaptic vagal connection to the spleen (Fig 1 B, C) cannot be
correct.

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
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relaying action potentials from vagus to spleen. Fortunately some clues in the literature
suggest a relevant mechanism. In another inflammatory model, Miao, Jänig & Levine
found that synovial plasma extravasation in response to bradykinin depended critically on
the presence of sympathetic nerve terminals, but not on their action potentials. Acutely
abolishing the activity of these sympathetic nerves by decentralization or locally applied
tetrodotoxin had no effect. However, cutting the nerves several days before the
experiment was effective. The latter allowed the nerve terminals to degenerate. An action
of the sympathetic nerve terminals that did not require action potentials was the logical
conclusion. Now, in the case of the spleen, only chronic denervation has been tested for
its effect on the anti-inflammatory action of vagal stimulation . This allows the terminals
to degenerate. Reserpine treatment, which also blocks the vagal action, depeletes
terminals of noradrenaline. We predict that the presence of noradrenaline-containing
terminals in the spleen will be sufficient to mediate the vagal anti-inflammatory action,
independently of any action potentials in the splenic nerve. That prediction (Fig 1 D)
remains to be tested.
The issue of how the influence of vagal stimulation reaches the spleen will be
addressed below.

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 synthesize acetylcholine, and these are present in the spleens of mice .
Without these T-cells (in nude mice, who lack functional T-cells), vagal stimulation had
no anti-inflammatory effect. But that effect could be at least partly restored to nude mice
by the adoptive transfer of acetylcholine-synthesizing T lymphocytes into these animals .
The non-neural origin of acetylcholine in the spleen explains at least one
conundrum. Neurally released acetylcholine is hydrolysed extremely rapidly by
cholinesterases. Only a continuing source of production, such as provided by these T-
cells, could explain why acetylcholine levels in the spleen continue to rise over 15
minutes after the cessation of nerve stimulation (see Rosas-Ballina et al., 2011, figure 1).
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It also provides a likely mechanism for non-neural communication from the vagus to the
spleen.

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 .
Its ability to do so is enhanced during systemic inflammation . The vagus, though it does
not innervate the spleen, provides extensive innervation to the gastrointestinal tract,
where there are substantial depots of secondary lymphoid tissue . Indeed, there is
substantial innervation by postganglionic enteric neurons associated with immune cells in
the lymphoid tissue of the gut . We postulate that stimulating vagal efferent fibres, and/or
antidromically activating vagal afferent fibres, somehow stimulates one or more of these
depots into mobilizing lymphocytes, including acetylcholine-synthesizing T-cells. Once
mobilized, a proportion of these would be sequestered by in the spleen. We are unaware
of any direct evidence that vagal stimulation mobilizes cells from the gastrointestinal
tract, but it seems plausible in the light of evidence that it can mobilize lymphocytes from
the thymus .
These proposals are shown schematically in Figure 1 D. The relevant evidence is
summarised below.

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.
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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 peripheral end of the cut cervical vagus suppresses
local and systemic inflammation.
4) The anti-inflammatory action of stimulating the peripheral end of the cut vagus
does not work in mice lacking the α7 nicotinic receptor subunit.
5) Nor does the anti-inflammatory action of vagal stimulation work in nude mice,
who lack T lymphocytes. Adoptive transfer of ACh-synthesizing T lymphocytes
into nude mice restores some vagal anti-inflammatory action.

This evidence tells us that experimental activation of vagal efferent pathways (and/or
perhaps antidromic activation of vagal afferent fibres) gives rise to suppression of
inflammation in a manner that depends on nicotinic receptors containing the α7 subunit
and on acetylcholine-synthesizing T lymphocytes. The site of the essential nicotinic
receptor was not established, though splenic macrophages and sympathetic ganglion
cells have both been suggested. The cholinergic link appears to be non-neural in origin.

6) Removal of the spleen substantially reduces the plasma TNFα response to

systemic LPS (achieving levels similar to those resulting from vagal stimulation
in intact animals). Stimulating the vagus after splenectomy lowers the TNFα
response no further .

This indicates that the spleen is the main source of circulating TNFα due to challenge
with systemic LPS. Vagal stimulation acts to inhibit that production by the spleen.

7) Destruction of the noradrenergic splenic nerves or depletion of terminal

noradrenaline content by reserpine blocks the anti-inflammatory action of vagal
stimulation .
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This demonstrates that the presence of noradrenaline-containing nerve terminals in the

spleen is necessary for the anti-inflammatory action of vagal stimulation.

8) There is no disynaptic link from the vagus to the spleen via the splenic nerves.
Stimulating the vagus does not drive action potentials in the splenic nerves .
9) Direct stimulation of the splenic nerves suppresses systemic inflammation even in
mice lacking the α7 nicotinic receptor subunit (when vagal stimulation does not
work).

These findings indicate that vagal stimulation acts on the spleen by a non-neural pathway.
The (non-neural) vagal action on splenic TNFα production in systemic inflammation
depends on the presence of noradrenergic sympathetic terminals in the spleen, but
evidently not on action potentials from the parent neurons. A suggested mechanism to
take account of the above findings is illustrated in Fig 1D. It is testable. As a counterpart,
the effectiveness of direct stimulation of the splenic nerves demonstrates that there is a
distinct sympathetic antiinflammatory pathway, whose action is mediated by action
potentials in the splenic nerves, and does not require the α7 nicotinic receptor subunit.

The Inflammatory Reflex

The term ‘Inflammatory Reflex’ was introduced a decade ago by Tracey in an
influential review . 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 lethal or high
sublethal doses of LPS to rodents. The anti-inflammatory action of vagal stimulation has
been repeatedly demonstrated in this model .
Any reflex can be considered as having an afferent pathway, a central processing
component and an efferent pathway. Two other reflex responses to systemic LPS have
been well studied: fever and the activation of the hypothalamic-pituitary-adrenal (HPA)
axis. Ideas on the role of the vagus as an afferent pathway for these responses have
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evolved over the years, reflecting successive control for the confounding factors that
accompany chronic subdiaphragmatic vagotomy (principally malnutrition). Current
opinion , indicates that when confounding factors are accounted for, vagotomy has no
effect on responses to LPS, with the possible exception of when minimal doses evoke
monophasic fever. When higher doses of LPS are given intravenously, it is clear that the
main afferent pathways driving fever and the HPA axis are humoral, and involve
prostaglandin E2 as the key mediator acting in the brain . For the inflammatory reflex,
the afferent pathways are not well worked out, but it is likely that similar considerations
apply.
The topic that concerns us here is the efferent pathway of the inflammatory reflex.
It has been stated on several occasions that the efferent arm of the inflammatory reflex is
the cholinergic anti-inflammatory pathway . If that is so, the stimulus that triggers
inflammation (e.g. i.v. LPS) must reflexly activate vagal efferent fibres with an anti-
inflammatory action. The critical test of this idea is to cut the vagi, which should then
remove that anti-inflammatory action - worsening the inflammation. Does this happen?
The original study demonstrating the inhibitory effect of vagal stimulation on
systemic inflammation found that cutting the vagi caused a 40% increase in the plasma
TNFα of rats given LPS (15 mg/kg i.v). However, that study also found that the plasma
corticosterone levels were 33% lower in vagotomised animals. It is therefore uncertain
how much of the enhanced inflammatory response could be attributed to removal of
vagal efferents and how much to reduced glucocorticoid restraint on inflammatory
processes . A later study on rats from the same laboratory found that bilateral vagotomy
caused a non-significant increase in the plasma TNFα response to 10 mg/kg i.v. LPS .
Finally, a study on rats from another laboratory found that the plasma TNFα response to 8
mg/kg i.v. LPS was significantly decreased (~ 50%) after vagotomy . In sum, no clear
case has been made that the inflammatory response to high doses of i.v. LPS is increased
by vagotomy: the evidence is, at best, equivocal.
In summary, we may conclude that while the vagi mediate the anti-inflammatory
response to pharmacological stimuli – CN1493 and centrally acting muscarinic agonists –
no good evidence supports the view that they constitute the efferent pathway of a reflex
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triggered by inflammation. The cholinergic antiinflammatory pathway and the

inflammatory reflex are evidently distinct processes, and should not be conflated.

Legend

Figure 1: The evolution of the Cholinergic antiinflammatory pathway

A: (2002) shows the original formulation, in which vagal efferent fibres are
proposed to act directly on immune cells (principally macrophages) to suppress their
production of TNFα and other inflammatory mediators .
B: (2008) The discovery of the importance of the spleen and the splenic nerves
and the lack of direct vagal innervation of the spleen prompted this revision. Here, the
preganglionic vagal fibres are postulated to synapse with postganglionic splenic
(sympathetic) neurons in the celiac ganglion. One suggested site for the essential α7-
containing nicotinic receptor was on the postganglionic splenic neuron .
C: (2011). This version incorporates the recognition of the essential role of
acetylcholine-synthesizing T-cells. Here, the essential α7-containing nicotinic receptor is
placed in the spleen, on splenic macrophages .
D: (2013) shows the model proposed here. It recognizes that the link from the
vagus to the spleen is non-neural. In this version the essential α7-containing nicotinic
receptor is placed not on the cell bodies but on the peripheral terminals of the splenic
sympathetic nerves. When stimulated by acetylcholine from incoming T-cells, they
release noradrenaline, which then acts on beta adrenergic receptors on splenic
macrophages to suppress their production of TNFα. No action potentials are required.
If, on the other hand, action potentials are generated in the splenic nerve by direct
stimulation , the anti-inflammatory action bypasses the need for α7-containing nicotinic
receptors .
Abbreviations: ACh, acetylcholine; β, beta adrenergic receptor; ChAT+, Choline
acetyl transferase positive, i.e. ACh-synthesizing, T cell; LPS, lipopolysaccharide; N,
nicotinic cholinergic receptor; NA, noradrenaline; TNFα, tumour necrosis factor alpha.

Acknowledgements
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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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Figure 1: The evolution of the Cholinergic antiinflammatory pathway

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