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Adv Physiol Educ 38: 135–139, 2014;
doi:10.1152/advan.00094.2013.
Refresher Course
Neural control of the immune system
Eva Sundman1 and Peder S. Olofsson2
1
Section for Anesthesiology and Intenstive Care Medicine, Department of Physiology and Pharmacology, Karolinska
Institutet, Karolinska University Hospital, Stockholm, Sweden; and 2The Feinstein Institute for Medical Research, Laboratory
of Biomedical Sciences, Manhasset, New York
Submitted 16 August 2013; accepted in final form 25 March 2014
immunoneurology; inflammation; vagus nerve; homeostasis; immunity
of mammalian physiology is that the nervous
system supports homeostasis by modulating the function of
organ systems. The basic organizational unit of the nervous
system is the reflex arc, composed of sensory (afferent) neurons that report to the central nervous system (CNS) and motor
(efferent) neurons that project regulatory signals to target
tissues. CNS integration of information allows for a purposeful
and rapid adaptation to changing demands on the organism
through autonomic reflexes. For example, the baroreflex regulates heart rate (HR) and blood pressure to optimize organ
perfusion and delivery of O2 and nutrients (58).
Although reflex physiology has been a field of extensive research, limited attention has been given to neural control of
inflammation and immunity. However, recent advances in neuroscience and immunology have revealed that neural reflexes
regulate immune system function in a range of species, from
evolutionarily ancient animals, i.e., Caenorhabditis elegans, up
to complex mammals(43, 56). These new insights have identified novel potential therapeutic targets for treatment of inflammatory disease and spawned exploration of bioelectronic
medicine, i.e., therapeutic delivery of electrical impulses that
activate nerves for treatment of disease (18). Applications of
the knowledge on neural reflex regulation of inflammation are
now evolving from experimental animal models to human
clinical trials (9, 30, 43).
A PRINCIPLE
Nerves Sense Inflammation and Interact With Leukocytes
Inflammation is a key process in mammalian defense against
pathogens and in wound healing. Molecular products of miAddress for reprint requests and other correspondence: P. S. Olofsson, The
Feinstein Institute for Medical Research, Laboratory of Biomedical Sciences,
350 Community Drive, Manhasset, NY 11030 (e-mail: ps.olofsson@gmail.
com).
crobial invasion and tissue damage are detected by pattern
recognition receptors (PRRs), which activate cells in the innate
immune system, e.g. macrophages. This early response gives
rise to a cascade of events aimed to clear pathogens and
ultimately restore health, and includes the production of proinflammatory cytokines and recruitment of leukocytes (Fig. 1).
The initial process promotes the classic symptoms of localized
inflammation, including swelling, redness, and loss of function,
and may progress to include systemic responses mediated by
the CNS, such as fever, anorexia, and fatigue (66). Because
excessive inflammation and cytokine production in itself can
cause tissue damage, nonresolving inflammation, inflammatory
diseases, shock, and even death (40, 61), it is essential that the
inflammatory response is tightly regulated and controlled.
Multiple control mechanisms that balance proinflammatory
mechanisms have been described, for example, release of
inhibitory cytokines and soluble cytokine receptors as well as
activation of regulatory lymphocyte subsets (39). Interestingly,
PRRs (e.g., Toll-like receptors and nucleotide-binding oligomerization domain receptors) and receptors for cytokines
and prostaglandins are also expressed by sensory neurons (13)
and provide a molecular mechanism for the CNS to acquire
information on localized inflammation in the periphery. Indeed, sensory nerves can respond to the presence of microbial products independent of immune activation (12). Since
sensory nerves form a dense network throughout the external surfaces of the body, it has been suggested that this
innervation provides an anatomic basis for precise sensing
by the CNS of pathogen invasion, tissue damage, and
inflammation (13). Reciprocally, a range of immune cells
express receptors for neurotransmitters, including dopamine, ACh, and norepinephrine, which can regulate leukocyte activity and differentiation (16, 29, 44, 47, 67). Autonomic nerves innervate lymphoid tissue and other organs
and regulate immune responses (22, 28, 38, 55). Hence, an
anatomic and molecular framework for sensing and regulating immune system activity in a reflexive manner is in place.
The Inflammatory Reflex
Important insights into the neural control of inflammation
have come from the study of a prototypical example of a neural
immune-regulatory circuit termed the “inflammatory reflex.”
In this reflex, afferent signals transmitted through the vagus
nerve are processed in the CNS and culminate in efferent vagus
nerve activity that regulates macrophage cytokine release in the
spleen (60). Our current understanding of this reflex is based
on a number of seminal discoveries. Watkins et al. and other
research teams (10, 49, 65) found that the fever response to low
doses of IL-1␤ injected into the intraperitoneal cavity of rats
requires an intact vagus nerve, because animals with a subdia-
1043-4046/14 Copyright © 2014 The American Physiological Society
135
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Sundman E, Olofsson PS. Neural control of the immune system. Adv
Physiol Educ 38: 135–139, 2014; doi:10.1152/advan.00094.2013.—Neural
reflexes support homeostasis by modulating the function of organ
systems. Recent advances in neuroscience and immunology have
revealed that neural reflexes also regulate the immune system. Activation of the vagus nerve modulates leukocyte cytokine production
and alleviates experimental shock and autoimmune disease, and recent
data have suggested that vagus nerve stimulation can improve symptoms in human rheumatoid arthritis. These discoveries have generated
an increased interest in bioelectronic medicine, i.e., therapeutic delivery of electrical impulses that activate nerves to regulate immune
system function. Here, we discuss the physiology and potential
therapeutic implications of neural immune control.
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NEURAL CONTROL OF THE IMMUNE SYSTEM
Regulatory
mechanisms
Infection
Specialized T Cells Are an Integral Component of the
Inflammatory Reflex
Health
Bacteria
Viruses
NLR
TLRs
Tissue injury
Cytokines
Inflammation
Sickness
Syndrome
Non-resolving
inflammation
Swelling
Loss of function
Tissue injury
Pain
Anorexia
Fatigue
Shock
Fever
Cell debris
Macrophage
Rheumatoid arthritis
Atherosclerosis
Inflammatory bowel disease
Multiple sclerosis
Certain cancers
phragmatically severed vagus nerve fail to develop a pyrexic
response to the injected cytokine. Moreover, injection of IL-1␤
into the portal vein in rats gives rise to increased afferent
activity in the vagus nerve and increased activity in the splenic
nerve, but not when the hepatic branch of the vagus nerve had
been ablated (41). Thus, signaling in the vagus nerve plays a
role in the systemic response to cytokines. Tracey and colleagues (8) found that CNI-1493, a tetravalent guanylhydrazone with anti-inflammatory effects, is significantly more potent when given directly in the brain (intracerebroventricularly)
compared with intravenous dosing and that an intact vagus
nerve is required for its effect. These findings indicate that
signals originating in the CNS can travel through the cholinergic vagus nerve and regulate inflammation in the periphery.
Indeed, electrical stimulation of the vagus nerve significantly
reduces systemic TNF levels and prevents shock in experimental endotoxemia, whereas surgical ablation of the vagus nerve
has the opposite effect in this model (9).
The spleen is a major source of systemic TNF in endotoxemia, and it has been convincingly demonstrated that electrical
vagus nerve stimulation (VNS) can significantly reduce cytokine production in the spleen. However, the vagus nerve does
not directly innervate the spleen. It travels to the coeliac
ganglion, where the adrenergic splenic nerve arises. Electrical
stimulation of the splenic nerve reduces splenic cytokine production (28), and the splenic nerve is necessary for vagus
nerve-mediated inhibition of TNF release from splenic macrophages (51). Furthermore, activation of cholinergic ␣7-nicotinic ACh receptors (␣7nAChRs) is required for vagus nervemediated inhibition of their TNF release (64). Given that nerve
fibers in the spleen lack the machinery to produce ACh, how
are signals in this conduit relayed to cholinergic receptors in
the spleen?
Therapeutic Effects of Electrical VNS
Activation of signaling in the inflammatory reflex by
electrical nerve stimulation or pharmacological means not
only attenuates TNF production but can also treat a variety
of diseases with an inflammatory component in animal
models (for a review, see Ref. 2). For example, activation of
the efferent arm of the inflammatory reflex reduces mortality
after cecal ligation and puncture (CLP; a sepsis model),
whereas disabling vagus signaling increases mortality (7,
24, 45). Central activation of the inflammatory reflex ame-
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Fig. 1. The immune response. Invasion and tissue injury are sensed by
pattern recognition receptors that activate innate immune cells. This early
response gives rise to a cascade of events, including the release of
proinflammatory cytokines and recruitment of leukocytes, aimed to clear
pathogens and ultimately restore health. In addition to the local tissue
response with swelling and redness, fever, anorexia, and fatigue may
develop, indicating that the inflammation is sensed by the central nervous
system (CNS). It is crucially important that the immune response is
regulated within narrow limits and terminated as soon as the threat has been
properly addressed. Otherwise, the reaction may cause excessive tissue
damage, nonresolving inflammation and inflammatory disease, and even
death. A number of regulatory mechanisms are in place, including suppressor lymphocytes, inhibitory cytokines, and neural reflex circuits. Pattern
recognition receptors are indicated as Toll-like receptors (TLRs) and
nucleotide-binding oligomerization domain receptors (NLRs).
Despite the lack of splenic cholinergic innervation, the
spleen is known to contain the neurotransmitter ACh (15).
The source of this ACh has not been extensively studied.
Pioneering work by Kawashima and colleagues (20, 21, 48)
showed that some lymphocytes, including T cells, express
the enzyme choline acetyltransferase (ChAT) and are capable of ACh biosynthesis. We discovered that electrical VNS
fails to inhibit systemic TNF release in endotoxemia in T
cell-deficient nude mice (52). Interestingly, lymphocytes are
found in close apposition to adrenergic nerve endings in the
spleen (19, 52), and T cell expression of adrenergic receptors is required for the integrity of the efferent arm of the
inflammatory reflex (63). This proximity of nerves and
ChAT⫹ lymphocytes in the spleen and the expression of
adrenergic receptors on ChAT⫹ T cells (52) provide a basis
for direct signals between nerves and splenic lymphocytes.
Adoptive transfer of ChAT⫹, but not ChAT⫺, T lymphocytes to nude mice restores the inhibitory effect of VNS on
TNF release (52). Collectively, these data support that the
ACh production and release required for inhibition of TNF
in the spleen is provided by ChAT⫹ T lymphocytes.
Macrophages in the spleen are a major source of systemic
TNF in experimental endotoxemia (25, 51). Monocytes and
macrophages express cholinergic receptors and respond to
cholinergic agonists with reduced release of proinflammatory
cytokines (4, 50). Expression of ␣7nAChRs is, furthermore,
essential for vagus nerve-mediated inhibition of TNF release in
endotoxemia and required for the macrophage response to
cholinergic agonists (64). Since ␣7nAChRs are expressed in
several organs, including the CNS and autonomic ganglia, it
was conceivable that the cholinergic signal required for the
integrity of the inflammatory reflex occurred outside the immune system and not in splenic macrophages. Experiments
with chimeric mice created by bone marrow transfer demonstrated that ␣7nAChR deficiency in nonbone marrow-derived
cells did not abolish vagus nerve inhibition of cytokine production in endotoxemia. In contrast, ␣7nAChR deficiency in
bone marrow-derived cells, including leukocytes, abolished the
inhibitory effect of VNS on TNF production (42). These
observations indicate that signaling through ␣7nAChRs on
macrophages in the spleen is essential for the integrity of the
inflammatory reflex.
Thus, electrical signals in vagus nerve fibers that terminate
in the celiac ganglion (5) activate the splenic nerve to release
norepinephrine, which, in turn, activates ChAT⫹ T cells in the
spleen to release ACh and inhibit TNF release by activating
␣7nAChRs on macrophages (Fig. 2).
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NEURAL CONTROL OF THE IMMUNE SYSTEM
137
Afferent
Vagus Nerve
Efferent
Vagus Nerve
Infection
Celiac
Ganglion
Bacteria
NLR
Viruses
TLRs
Cell debris
Macrophage
α7nAChR
Splenic
nerve
Norepinephrine
Release
β2AR
Acetylcholine
Release
ChAT+ T cell
liorates colitis (26). VNS, as well as ␣7nAChR agonist
administration, ameliorates a range of experimental autoimmune diseases, including collagen-induced arthritis (2, 27,
62, 68, 69). In humans, analysis of HR variability (HRV)
has been used as a measure of vagus nerve activity (53).
Interestingly, HRV measurements upon hospital admission
have a predictive value for outcome in human sepsis (1, 11,
46). Vagus nerve activity, as measured by HRV, is also a
prognostic marker for ischemic cardiovascular disease (6,
14, 31, 35) and is reduced in autoimmune diseases, including rheumatoid arthritis (17, 32, 34, 54, 57). The findings on
the correlation of HRV to disease do not establish causality
of vagus activity for disease development but support the
notion that modulation of vagus nerve signals may treat
disease. Preliminary data from a phase II clinical trial of an
implantable electrical vagus nerve stimulator in patients
suffering from rheumatoid arthritis were recently presented
(30). In this study, the stimulator was activated by the
patient for ⬍5 min/day by passing a magnet over the
implanted device. Levels of disease activity score and Creactive protein levels in blood were significantly reduced
by the treatment and returned toward baseline levels when
treatment was halted. These findings are encouraging, since
they suggest that symptoms of rheumatoid arthritis and
inflammation may potentially be controlled and treated by
VNS in humans. Clinical trials of VNS as a treatment for
other inflammatory diseases, e.g., Crohn’s disease, are also
under way. It would be very interesting to investigate the
potential of VNS for the treatment of other debilitating
diseases with an inflammatory pathogenesis, including
atherothrombosis (23, 33).
Other Immune-Regulatory Neural Reflexes
In addition to the vagus nerve circuit described above, a
number of other neural immune control pathways have been
described. Electrical stimulation of the sciatic nerve has been
reported to improve outcome in experimental bacterial peritonitis (59). VNS reduces murine marginal zone B cell migration
and antigen production in the spleen in response to blood-borne
streptococci (37). VNS also reduces experimental inflammatory bowel disease in splenectomized animals, indicating that
discrete innervation by the vagus nerve regulates the inflammatory response at different locations (36, 43). Furthermore, in
experimental murine stroke, invariant natural killer T (iNKT)
cell migration in the liver is arrested in response to adrenergic
signals. This is a mechanism behind the increased susceptibility to fatal infections after stroke in mice, and blockade of the
adrenergic nerve signaling restores iNKT migratory activity
and reduces complications to infection in this model (67).
In addition, Arima and colleagues (3) showed in experimental
autoimmune encephalomyelitis, a mouse model of multiple sclerosis, that autoreactive T cells enter the CNS at a specific spinal
cord location. In this case, CNS access for T cells depends on
a reflex neural circuit originating in hindleg muscle contractions. These nervous signals promote vascular chemokine (C-C
motif) ligand 20 expression, which, in turn, facilitates T cell
entry into the CNS. Disease development in this model was
prevented by inhibition of the afferent nerve signals originating
in soleus muscle contractions that reach the spinal cord at this
specific lumbar location (3). It is conceivable that some of the
neural reflexes that regulate inflammation and immune cell
activity can be therapeutically modulated for the treatment of
clinical disease. Furthermore, monitoring of signals in the
neuronal circuits that regulate immune system activity may
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Cytokines
Tissue injury
Fig. 2. The inflammatory reflex. The current
understanding of the inflammatory reflex, an
immune-regulatory vagus nerve circuit, is that
sensory nerve fibers, e.g., afferent vagus nerve
branches, report on localized cytokine levels
and inflammation in the periphery. This information is processed in the brain stem, which
generates efferent signals that travel through
motor fibers in the vagus nerve and activate
the adrenergic splenic nerve, which releases
norepinephrine in the spleen. Specialized
choline acetyltransferase-expressing T cells
(ChAT⫹ T cells) release ACh in response to
norepinephrine and inhibit macrophage cytokine production by activating their ␣7-nicotinic ACh receptors (␣7nAChRs). ␤2AR, ␤2adrenergic receptors.
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NEURAL CONTROL OF THE IMMUNE SYSTEM
prove to be of diagnostic value in conditions with nonresolving
inflammation.
Conclusions
ACKNOWLEDGMENTS
The authors thank Dr. Ben Steinberg, Dr. Valentin A. Pavlov, and Dr.
Kevin J. Tracey for helpful comments.
GRANTS
This work was supported by funding from Svenska Läkaresällskapet.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
Author contributions: E.S. and P.S.O. prepared figures; E.S. and P.S.O.
drafted manuscript; E.S. and P.S.O. edited and revised manuscript; E.S. and
P.S.O. approved final version of manuscript.
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