Physiol Rev 98: 477–504, 2018

Published December 20, 2017; doi:10.1152/physrev.00039.2016

NEUROIMMUNE INTERACTIONS: FROM THE

BRAIN TO THE IMMUNE SYSTEM AND VICE
VERSA
Robert Dantzer

Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, Texas

Dantzer R. Neuroimmune Interactions: From the Brain to the Immune System and

L
Vice Versa. Physiol Rev 98: 477–504, 2018. Published December 20, 2017; doi:
10.1152/physrev.00039.2016.—Because of the compartmentalization of disci-
plines that shaped the academic landscape of biology and biomedical sciences in the
past, physiological systems have long been studied in isolation from each other. This
has particularly been the case for the immune system. As a consequence of its ties with pathology
and microbiology, immunology as a discipline has largely grown independently of physiology. Ac-
cordingly, it has taken a long time for immunologists to accept the concept that the immune system
is not self-regulated but functions in close association with the nervous system. These associations
are present at different levels of organization. At the local level, there is clear evidence for the
production and use of immune factors by the central nervous system and for the production and
use of neuroendocrine mediators by the immune system. Short-range interactions between im-
mune cells and peripheral nerve endings innervating immune organs allow the immune system to
recruit local neuronal elements for fine tuning of the immune response. Reciprocally, immune cells
and mediators play a regulatory role in the nervous system and participate in the elimination and
plasticity of synapses during development as well as in synaptic plasticity at adulthood. At the whole
organism level, long-range interactions between immune cells and the central nervous system allow
the immune system to engage the rest of the body in the fight against infection from pathogenic
microorganisms and permit the nervous system to regulate immune functioning. Alterations in
communication pathways between the immune system and the nervous system can account for
many pathological conditions that were initially attributed to strict organ dysfunction. This applies in
particular to psychiatric disorders and several immune-mediated diseases. This review will show
how our understanding of this balance between long-range and short-range interactions between
the immune system and the central nervous system has evolved over time, since the first demon-
strations of immune influences on brain functions. The necessary complementarity of these two
modes of communication will then be discussed. Finally, a few examples will illustrate how dysfunc-
tion in these communication pathways results in what was formerly considered in psychiatry and
immunology to be strict organ pathologies.

I. INTRODUCTION 477 monly studied in different physiological systems using the

II. NEURAL AND HORMONAL ... 479 same tools. This is the case, for instance, for purinergic
III. IMMUNE INFLUENCES ON THE ... 485 signaling, which is investigated by immunologists for its
IV. ALTERATIONS IN THE ... 491 role in macrophage function and plasticity (57) and by neu-
V. CONCLUSIONS AND PERSPECTIVES 496 robiologists for its regulatory activity on synaptic plasticity
(203). Blurring of the boundaries between disciplines is
probably the main outcome of this wave of research. How-
I. INTRODUCTION ever, this situation is still relatively new, and the transition
to it has been very progressive.
Our understanding of physiology has benefited greatly from
the advances in molecular biology that have been at the This is well reflected in the history of the research efforts in
origin of the explosive development of genetics and -omic neural–immune interactions (TABLE 1) (1). What was ini-
techniques. What used to be a rarity a few decades ago, tially of interest to only a few practitioners in psychoso-
studying the expression and function of a given molecule matic medicine—the influence of personality factors and
within a different physiological system from the one in emotional states on sensitivity to disease, or more generally
which it was first identified, has now become the norm. the interrelationships among mind, body, and environment
Communication signals and signaling pathways are com- in health and disease— became an object of scientific inves-

0031-9333/18 Copyright © 2018 the American Physiological Society 477

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 ROBERT DANTZER
Table 1. The early decades of research that shaped the field
of neuroimmune interactions
Early Neuroimmune Research
1. The psychosomatic approach:
Psychological factors and emotions influence disease
onset and progression (allergies, peptic ulcer, cancer,
autoimmune diseases, infectious diseases)
2. The biobehavioral approach:
Experimental stressors impact immune functions (1964:
Solomon proposes the term “psychoimmunology”)
The immune system can be modulated by conditioned
stimuli (Metalnikov and Chorine, 1926; Ader, 1974)
3. The cellular communication approach:
Immune cells express neurotransmitter receptors
(Szentivanyi, 1958; Hadden, 1970–5; Pert, 1985)
Immune cells produce brain and pituitary peptides
(Blalock, 1980)
4. The neuroanatomical approach:
Innervation of the spleen and other lymphoid organs by
the autonomic nervous system (Felten, 1980)
5. The effect of immune factors on the neuroendocrine
system:
Interleukin-1 activates the hypothalamic-pituitary-adrenal
axis by acting in the brain (Besedovsky and Del Rey,
1975)
tigation in the 1950s, when it was brought into the labora-
tory to be subjected to a reductionist approach (139). Not
surprisingly, retrospectively, but at the time difficult for hard-
core pathologists to admit, biobehavioral factors, in the form
of exposure to well-defined stressors, were found to influence
the initiation and progression of various infectious and nonin-
fectious diseases in animal models of pathology. Once it be-
came possible to assess immune functions in a routine manner
using techniques borrowed from clinical immunology, these
influences were ascribed to modulation of immune responses
by activation of the stress pathways. The predominant stress
pathways that were investigated were the hypothalamic-
pituitary-adrenal (HPA) axis, the activation of which re-
sults in the release of cortisol or corticosterone (depending
on the species), and the sympathetic nervous system, the
activation of which results in the release of epinephrine and
norepinephrine.
The study of psychological modulation of immunity, ini-
tially conducted at Institut Pasteur in Paris, France in the
1920s using Pavlovian conditioned stimuli (157), was re-
vived in the 1970s by Ader and Cohen (2), who rediscov-
ered the phenomenon of conditioned immunosuppression.
Working at the University of Rochester Medical Center,
they showed that it is possible to increase the immunosup-
pressive effect of cyclophosphamide by presenting rats with
the taste of a saccharin solution previously paired with ex-
posure to the poisonous side effects of cyclophosphamide
(2). These were key experiments that indirectly revealed the
existence of an intricate network of bidirectional commu-
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nications between the central nervous and the immune sys-
tems. Such communication pathways had been suspected
before but not yet demonstrated. Therefore, they were not
amenable to mechanistic analysis.
The field of research that studies the basic aspects of neural–
immune interactions was variously labeled neuroimmuno-
modulation, neuroimmunoendocrinology, or psychoneuro-
immunology, depending on which scientific discipline pre-
dominated at the time. However, this new wave of
interdisciplinary research gained momentum in the scien-
tific community at large only when the pathways of com-
munication between the nervous system and the immune
system were elucidated. In a nonconcerted effort, neuro-
anatomists demonstrated the existence of a sympathetic in-
nervation of primary and secondary lymphoid organs (71),
neuroendocrinologists described the expression and func-
tion of neuroendocrine receptors on immune cells (95, 177),
and cell biologists showed that activated immunocytes ex-
press and release molecular factors previously identified in
the neuroendocrine system, such as adrenocorticotrophin,
which is processed from proopiomelanocortin in lympho-
cytes in the same manner as in the anterior pituitary (212,
213). The emphasis on brain-to-immune, rather than im-
mune-to-brain, communication pathways was mainly due
to the active involvement of neuroendocrinologists in the
field and to the progress made in the elucidation of the
chemical nature and receptor mechanisms of most neuroen-
docrine factors (93).
Although the existence of an immune-to-brain communica-
tion pathway had been inferred by Besedovsky et al. (17),
whose elegant physiological studies demonstrated activa-
tion of the HPA axis and the sympathetic nervous system
during the peak antibody response in mice vaccinated with
a T-cell antigen, the molecular nature of this communica-
tion pathway took longer to be elucidated. Cloning and
recombinant expression of cytokines, the autocrine and
paracrine communication factors between immune cells,
did not take place before the early 1980s (60). The ability of
the first cloned cytokine interleukin (IL)-1␤ to activate the
HPA axis and induce some of the physiological changes
observed in a mouse model of antibody response to sheep
red blood cells was reported in 1986, shortly after the dem-
onstration of the pyrogenic activity of this cytokine (16).
As previously presented in Physiological Reviews, basic
communication mechanisms between the nervous and im-
mune systems include the immune production and function
of neuroendocrine peptide hormones (22), the effects of
neuroendocrine hormones on the immune system and the
innervation of lymphoid organs by the sympathetic nervous
system (142), and the regulatory effects of cytokines on the
HPA axis (232). The objective of this review is not to update
this information but to introduce a new perspective: the
fascinating complementarity between short-range and long-
 NEUROIMMUNE INTERACTIONS
range communication mechanisms between the nervous
and the immune systems.
Studies of long-range communication mechanisms were ini-
tially favored, certainly because of the strong predominance
of neuroendocrinology and neuroanatomy in the emerging
field of psychoneuroimmunology. Communication from
the nervous system to the immune system was believed to
take place exclusively via circulating hormones produced
by the neuroendocrine system (e.g., cortisol, but also
growth hormone and prolactin) and via neurotransmitters
(e.g., epinephrine and norepinephrine) released in the vicin-
ity of immune cells by nerve endings in primary and second-
ary lymphoid organs. However, the discovery that immune
cells can themselves produce and release neuroendocrine
factors and neuromediators led to a shift in interest from
long-range to short-range communication pathways.
Similarly, communication from the immune system to the
brain was initially seen as involving circulating immune
factors acting indirectly on the brain via the formation of
brain-penetrant molecules (prostaglandins) in brain areas
where the blood-brain barrier is leaky, the so-called circum-
ventricular organs. This was how endogenous pyrogens
were perceived as being responsible for the development of
the fever response to infectious pathogens. It took time for
neurobiologists to realize that brain innate immune cells
actually produce the same cytokines as those originally
characterized as endogenous pyrogens and that these lo-
cally produced cytokines are responsible for the various
components of the response of the host to infection. It took
even longer to recognize that cytokines produced locally by
brain cells are responsible for intricate functional and struc-
tural interactions between endothelial cells, glia, and neu-
rons.
II. NEURAL AND HORMONAL INFLUENCES
ON THE IMMUNE SYSTEM
A. Innervation of Lymphoid Organs:
Sympathetic Versus Parasympathetic
Innervation
There is much anatomic and functional evidence for a role
of the autonomic nervous in the regulation of immunity
(142). Most of the neuroanatomical studies on innervation
of lymphoid organs were carried out during the 1970s–
1980s. They revealed the existence of a dense sympathetic
innervation of all lymphoid organs. Sympathetic nerves
travel with the vasculature but separate from it when enter-
ing lymphoid organs. They terminate in close contact with
parenchymal T lymphocytes and plasma cells, forming
what has been termed “neuroeffector junctions” (71). The
nerve fibers that innervate lymphoid organs contain various
neuropeptides that are colocalized or not with norepineph-
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rine, including vasoactive intestinal peptide, neuropeptide
Y, substance P, Met-enkephalin, and neurotensin.
Most peripheral organs in the body are innervated by
branches of both the sympathetic and the parasympathetic
nervous systems. The immune system is apparently an ex-
ception: no neuroanatomical evidence exists for a parasym-
pathetic or vagal nerve supply to any immune organ, with
the possible exception of lymphoid tissue in the respiratory
and alimentary tracts (164). This is in contrast to results
from earlier tracing studies of innervation (37), which were
subsequently corroborated by visualization of the synthe-
sizing enzyme choline-O-acetyltransferase and the degrada-
tion enzyme acetylcholinesterase, which act on the neu-
rotransmitter acetylcholine (36). However, these observa-
tions were dismissed because of the presence of artifacts in
the tracing studies that were caused by the spillover of large
doses of tracers (142, 164) and the existence of a nonneu-
ronal acetylcholine expression system in lymphocytes (79).
Lymphocytes contain all the components required to con-
stitute an independent, nonneuronal cholinergic system, in-
cluding acetylcholine, its synthesizing and degrading en-
zymes, and muscarinic and cholinergic receptors. The fact
that expression of the components of this nonneuronal cho-
linergic system varies during T-cell activation as well as in
response to cholinergic agents indicates that acetylcholine
synthesized by T cells can act as an autocrine or paracrine
factor (115).
The possibility of a parasympathetic innervation of lymphoid
organs was reexamined recently, thanks to a new neural-tract
tracing methodology based on specific labeling of choline
acetyltransferase-expressing cells by the tdTomato fluorescent
protein, which can be utilized in appropriate transgenic lines
of mice (81). Cholinergic innervation emanating from enteric
neurons was apparent only in the intestinal lamina propria of
the gastrointestinal tract. Cholinergic fibers were found to
come in close contact with macrophages, plasma cells, and
lymphocytes located in the intestinal mucosa, and to a lesser
degree with immune cells within the gut-associated lymphoid
tissue. Cholinergic innervation of the spleen is very sparse and
comes from a small subset of cholinergic sympathetic post-
ganglionic neurons located in the paravertebral and/or pre-
vertebral chains. These fibers are often associated with peri-
arteriolar catecholaminergic fibers. A few of them terminate
in lymphocyte-containing areas of the white pulp. Nonneu-
ronal choline acetyltransferase cells are clearly visible in the
spleen and consist mainly of B cells and fewer T cells.
Another factor of confusion in the identification of cholin-
ergic innervation of lymphoid organs is the existence of a
catecholaminergic-to-cholinergic transmission switch in
some sympathetic fibers influenced by signals, such as leu-
kemia inhibitory factor, produced by the innervated target.
Although this is a marginal phenomenon, it has been de-
scribed in particular for the sympathetic fibers that inner-
479
 ROBERT DANTZER

vate sweat glands in mammalian footpads (69) and the
periosteum (6). Because the density of catecholaminergic
neurons that innervate inflamed tissue decreases in patients
with rheumatoid arthritis, the possibility of a catechol-
amine-to-cholinergic transition of sympathetic nerve fibers
was investigated in a murine model of collagen-induced
arthritis. Cholinergic sympathetic fibers became apparent
several weeks after the induction of arthritis under the in-
fluence of leukemia inhibitory factor. However, cat-
echolaminergic-to-cholinergic transition only affected
those fibers that innervate healthy tissue adjacent to the
inflammatory tissue (217).
The remarkable saga of the anti-inflammatory cholinergic
reflex proposed by Kevin Tracey in the 2000s illustrates
very well the various ingredients of the controversy about
the parasympathetic innervation of lymphoid organs (171).
The saga began with the discovery of unexpected pharma-
cological properties of a new anti-inflammatory drug devel-
oped by Tracey for the treatment of sepsis, tetravalent gua-
nylhydrazone (CNI-1493). CNI-1493 was developed on
the basis of its ability to inhibit the production of tumor
necrosis factor-␣ (TNF) and other macrophage inflamma-
tory cytokines in response to sepsis induced by administra-
tion of lipopolysaccharide (LPS). Tracey discovered that
this lead compound was much more potent when injected
into the lateral ventricle of the brain than when adminis-
tered systemically (29). This finding was interpreted to in-
dicate that CNI-1493 activates a neural pathway that links
the brain to peripheral macrophages. This neural pathway
was claimed to be the vagus nerves, as cutting the vagus
nerves abrogated the anti-inflammatory activity of CNI-
1493, whereas electrically stimulating the peripheral end of
vagal nerves mimicked it (30).
Indifferent to the controversies surrounding the possible
existence of a parasympathetic innervation of lymphoid or-
gans, Tracey (231) proposed that cholinergic vagal nerves
act on macrophages to suppress the production of TNF and
other inflammatory mediators. This neural communication
pathway from the central nervous system to the immune
system was presented as being part of an anti-inflammatory
reflex whose afferent arm was the production of inflamma-
tory cytokines by activated innate immune cells (see sect.
III) and whose efferent arm was the activation of cholinergic
efferents downregulating cytokine production by innate im-
mune cells (FIGURE 1). Muscarinic cholinergic stimulation
was proposed to mediate the central component of the anti-
inflammatory pathway, whereas activation of nicotinic re-
ceptors containing an ␣7 receptor subunit mediated the
downregulatory effect of acetylcholine on macrophages
(242). What was still lacking in the characterization of this
anti-inflammatory pathway, however, was an anatomically
characterized target for the efferent vagal innervation
(137).
This target was proposed to be the spleen, as sectioning of
the splenic nerves abrogated the anti-inflammatory signa-
ture of splenic macrophages that developed in response to
vagal nerve stimulation (107). In the absence of a direct
cholinergic innervation of the spleen, these findings were
interpreted to indicate that sympathetic postganglionic
splenic nerves indirectly transmitted the cholinergic vagal
message to splenic macrophages (192). The problem was
that this neuroanatomic circuit implied an adrenergic, in-
stead of cholinergic, transmission of the neural message to
macrophages. The missing cholinergic link surfaced later,
with the discovery that T cells that produce and release
acetylcholine in the spleen could be called to the rescue

A B
Brain Brain

Afferent Efferent Afferent Efferent vagus

vagus vagus vagus Acetylcholine
Splenic nerve

Proinflammatory Acetylcholine Proinflammatory Noradrenaline

cytokines cytokines

T cell
Acetylcholine
Spleen Spleen
Activated macrophage Activated macrophage

FIGURE 1. Schematic representation of the inflammatory reflex. A: the initial model of the inflammatory
reflex that was proposed originally by Tracey (231). Proinflammatory cytokines released by activated innate
immune cells activate the afferent vagus nerves. This sensory input activates in a reflex-like manner neuronal
cell bodies of the efferent vagus nerves. The resulting activation of the dorsal vagal complex recruits the
efferent cholinergic vagus nerves that downregulate inflammation. B: the revised model of the inflammatory
reflex. The parasympathetic branch of the vagus nerves activates the splenic nerves. Activation of this
sympathetic nerve results in the recruitment of acetylcholine-producing T cells that downregulate inflammation.

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 NEUROIMMUNE INTERACTIONS
(FIGURE 1) (193). Microdialysis of the spleen and mass spec-
trometry analysis of the dialysate samples were used to
demonstrate that vagus nerve stimulation leads indirectly to
the release of acetylcholine in situ. The lack of an effect of
vagus nerve stimulation in nude mice lacking T cells, to-
gether with adoptive transfer experiments of acetylcholine
containing T cells to nude mice, confirmed the role of T
lymphocytes in the anti-inflammatory reflex. Still missing
was a demonstration that acetylcholine-containing T cells
expressed ␤2-adrenergic receptors and were located in close
proximity to sympathetic splenic nerves. This was subse-
quently confirmed by immunofluorescence analysis of
spleen sections in mice expressing enhanced green fluores-
cent protein under the control of transcriptional regulatory
elements for choline acetyltransferase (193).
Whether this last element of the puzzle puts a triumphant
final brick on the saga of the anti-inflammatory reflex (171)
is not yet certain. The existence of an indirect vagal inner-
vation of the spleen by splenic nerves has been disputed,
because vagal preganglionic neurons do not synaptically
connect to sympathetic postganglionic neurons, and vagal
nerve stimulation does not recruit splenic neurons (33).
These last negative findings are in accordance with the fea-
tures of the very sparse cholinergic innervation of the spleen
described above (81). An alternative is that stimulation of
the vagus nerves actually recruits lymphocytes, including
acetylcholine-synthesizing cells, from the lymphoid tissue
of the gut that is innervated by vagal nerves. These T cells
would then be able to migrate to various organs, including
the spleen (148), and exert there their local anti-inflamma-
tory activity. As pointed out by Besedovsky a few decades
ago, immune-cell trafficking and recirculation require a
tight control of blood supply to lymphoid organs, including
the spleen. Interactions between locally produced cytokines
and sympathetic nerve fibers contribute to this control (187,
188). During sepsis that drives the inflammatory reflex, as
studied by Tracey, there is a dramatic increase in splenic
blood flow. This increase is secondary to an inhibition of
the sympathetic vasoconstrictor tonus at the postganglionic
and prejunctional levels. This results in a decrease in the
release of norepinephrine, and possibly other neuromedia-
tors, by sympathetic nerve fibers in response to locally pro-
duced IL-1␤ (187). In other terms, nerve-driven changes in
functionality of immune cells in vivo could well be due to
cytokine-induced alterations in the blood supply of the lym-
phoid organ under investigation, especially when this lym-
phoid organ is devoid of lymphatic circulation, which is the
case with the spleen. This observation necessitates reexam-
ination of the importance of sympathetic nerve endings in
controlling immune cell trafficking, circulation, and hom-
ing.
In conclusion of this section, innervation of the lymphoid
organs is predominantly sympathetic. Parasympathetic in-
nervation of lymphoid organs appears to be limited to the
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gut lymphoid tissue. The possibility that innervation regu-
lates immune cell functionality by modulating blood supply
of lymphoid organs requires further investigation.
B. Influences of Catecholamines on Immune
Cells
Innate immune cells express the ␤2, ␣1, and ␣2 subtypes of
adrenergic receptors, whereas adaptive immune cells ex-
press primarily the ␤2 subtype of adrenergic receptor (164).
Activation of ␤2-adrenergic receptors triggers a signaling
cascade involving the formation of cAMP, which activates
either protein kinase A (PKA) or the guanine exchange pro-
teins directly activated by cAMP (EPACs) (124). PKA sig-
nals via cytoplasmic kinases such as p38 mitogen-activated
protein kinase (MAPK) or the cAMP response element-
binding protein (CREB) transcription factor. EPACs fur-
ther signal via the Rap family of small Ras-like GTPases.
Ligation of the ␤2 adrenergic receptor can also activate
␤-arrestins that connect to multiple signaling pathways, in-
cluding p38, extracellular signal-regulated kinase MAPKs,
and nuclear factor kappa-B (NF-␬B).
Not surprisingly, an abundant literature describes the in
vitro effects of various adrenergic receptors agonists and
antagonists on immune cells and the signaling pathways
involved in these effects. For adaptive immunity, most of
the research effort has focused on the consequence of acti-
vating ␤2-adrenergic receptors in CD4⫹ T cells, Th1, and B
cells. Th2 cells do not express ␤2-adrenergic receptors, at
least in the mouse system. Stimulation of ␤2-adrenergic
receptors usually inhibits T-cell responses, although activa-
tion effects have also been described. For instance, in vitro
exposure of CD4⫹ T cells to norepinephrine or terbutaline
decreased IL-2 production in response to polyclonal activa-
tion with anti-CD3 monoclonal antibody (185). However,
norepinephrine also promoted naive CD4⫹ T-cell differen-
tiation into Th1 cells that produced more interferon (IFN)-␥
than did nonexposed cells (224). In vivo studies show that
chemical sympathetic denervation decreases the intensity of
delayed-type hypersensitivity, confirming a positive role of
catecholamines in Th1 cell-driven immune responses (143).
In B cells, the signaling pathway activated by ␤2-adrenergic
receptor activation involves a PKA-dependent, CREB-me-
diated pathway that converges with that activated by CD86
ligation to enhance the magnitude of an immunoglobulin
(Ig) G1 response. Activation of ␤2-adrenergic receptors also
enhances the IgE response but via a PKA-dependent, hema-
topoietic tyrosine phosphatase/p38 MAPK-mediated path-
way (173).
Because macrophages and monocytes express ␣1-adrener-
gic, ␣2-adrenergic, and ␤2-adrenergic receptors, their re-
sponse to adrenergic stimulation is more complex. In gen-
eral, the production of inflammatory cytokines is inhibited
by ␤2-adrenergic receptor activation, whereas it is en-
481
 ROBERT DANTZER
hanced by ␣1-adrenergic or ␣2-adrenergic receptor stimu-
lation (108, 110, 173, 215). However, adrenergic stimula-
tion also promotes myeloid cell recruitment and migration
to the site of injury, such that ␤2-adrenergic receptor antag-
onism might be beneficial. This is the case, for instance, in
mice submitted to repeated episodes of social defeat. Acti-
vation of ␤2-adrenergic receptors facilitates the recruitment
and trafficking of monocytes to the brain, resulting in pro-
longed activation of microglia and development of anxiety-
like behavior (250).
It is important to note that this effect of ␤2-adrenergic re-
ceptor activation on egress of monocytes from the bone
marrow is opposite to that observed on egress of lympho-
cytes from lymph nodes (163). In the latter case, ␤2-adren-
ergic receptor activation actually enhances retention of lym-
phocytes into lymphoid organs via chemokine receptors
(CC-chemokine receptor 7 for B cells and CXC-chemokine
receptor type 4 for T cells). Catecholamines acting on en-
dothelial cell adhesion molecules and chemokines produce
a similar dissociation in the modulation of the innate and
adaptive immune system during the dark-light cycle. This
dissociation is orchestrated by molecular clocks via adren-
ergic nerves (155, 202). Periods of activity associated with
high adrenergic tone are characterized by increased recruit-
ment of myeloid cells in tissues and sequestration of lym-
phocytes from general circulation into lymphoid organs. As
proposed by Scheiermann et al. (202), this would help the
innate immune system to be prepared for higher risk of
infection during the active phase of the cycle while keeping
the adaptive immune system at bay.
In addition to serving as coordination molecules between
physiological and immune processes when released from
autonomic nerves, catecholamines can serve other roles
when produced locally (134). Epinephrine and norepineph-
rine are produced and released by normal T cells and exert
their functions in an autocrine or paracrine manner via
classic adrenergic receptors on T cells. Lymphocytes con-
tain the machinery to synthesize and degrade cat-
echolamines, and they produce and release more cat-
echolamines when activated (147, 182). This is particularly
the case in lymphocytes from the mesenteric lymph nodes
(182), where catecholamines modulate lymphocyte traf-
ficking, local vascular perfusion, cytokine production, and
functional activity of lymphocytes.
Phagocytic cells (macrophages and neutrophils) also are
able to release high levels of epinephrine and norepineph-
rine when activated. This is associated with enhanced ex-
pression of catecholamine synthesizing and degrading en-
zymes (73). Blockade of ␣2-adrenoreceptors, but not ␤2-
adrenoreceptors, in a model of inflammation-induced lung
injury reduced the intensity of vascular leakage, whereas
administration of an ␣2-adrenergic agonist had the oppo-
site effect. Experiments showing that depletion of T cells
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and administration of reserpine to achieve sympathetic de-
nervation did not alter the effects of ␣2-adrenergic agents
eliminated the possibility that T cells or sympathetic inner-
vation produce these effects. In addition, blockade of ty-
rosine hydroxylase or dopamine-␤-hydroxylase diminished
the inflammatory response, whereas inhibition of the cate-
cholamine-O-methyl transferase enzyme increased lung in-
jury. These results were interpreted by the authors to suggest
that the phagocytic system can function as a diffusely ex-
pressed adrenergic organ. Enhancement of the local inflamma-
tory response by phagocyte-produced catecholamines was
found to be mediated by increased production of inflamma-
tory mediators via activation and translocation of NF-␬B (74).
C. Glucocorticoids
1. Anti-inflammatory versus proinflammatory activity
of glucocorticoids
In line with the original observation by Selye of an involu-
tion of the thymus and other lymphoid organs in response
to stress (205) and the subsequent demonstration of the
immunosuppressive effects of glucocorticoids (101), gluco-
corticoids have traditionally been seen as the hormonal me-
diators of the immunosuppressive effects of stressors. We
will not delve into the details of the vast literature on the
effects of stress on immunity, as this topic has been re-
viewed on several occasions and it is not directly relevant to
the present review (3, 9, 160, 169, 204, 220).
Glucocorticoids act on their cellular targets by binding to
glucocorticoid receptors (GRs). GRs normally reside in the
cytosol in the form of a protein complex that brings to-
gether heat-shock proteins and FK506 binding protein 52.
Upon binding to their ligand, GRs dissociate from this com-
plex to form monomers or dimers and translocate to the
nucleus The anti-inflammatory effects of glucocorticoids
are mediated by transcriptional repression following nu-
clear translocation and tethering of monomeric GRs to the
glucocorticoid-response elements of transcription factors
such as NF-␬B, activator protein (AP)-1, and IFN-regulat-
ing factor-3 (234). This results in the downregulation of
genes coding for inflammatory mediators, enzymes, and
adhesion molecules. Although the hypothesis is still contro-
versial, GR dimerization and transactivation are thought to
play an important role in the anti-inflammatory activity of
glucocorticoids. This phenomenon is illustrated by data ob-
tained in GR(dim/dim) mutant mice that show reduced GR
dimerization and increased sensitivity to TNF-induced in-
flammation, and to experimental models of sepsis induced
by LPS or cecal ligation and puncture (123, 235).
Glucocorticoids can be proinflammatory under certain con-
ditions. This effect can be secondary to the selection of
corticoid-resistant inflammatory cells, such as pathogenic
Th17 cells that overexpress IL-23 receptor and multidrug-
 NEUROIMMUNE INTERACTIONS
resistance protein and that are found in inflamed gut tissue
from patients with Crohn’s disease (186). The proinflam-
matory effect of glucocorticoids may also result from inhi-
bition of the production and release of anti-inflammatory
factors, or conversely from enhanced production and re-
lease of proinflammatory mediators. In the first case, dexa-
methasone administered 24 h before LPS was found to en-
hance the placenta’s proinflammatory cytokine response to
LPS as a consequence of the inhibition of lipoxin A4 syn-
thesis (255). In the second case, it is the dose of glucocorti-
coids that makes the difference: as mentioned above, phys-
iological glucocorticoid levels can be proinflammatory in
some circumstances, whereas high or pharmacological lev-
els are anti-inflammatory. For instance, low doses of gluco-
corticoids increase the production of macrophage migra-
tion inhibitory factor, and this effect is sufficient to override
glucocorticoid-mediated inhibition of cytokine production
and release by LPS-stimulated monocytes (39).
The proinflammatory effects of endogenous levels of corti-
costeroids have been demonstrated in the brain (214). As in
the placenta, these effects are observed only if the glucocor-
ticoid response occurs ahead of the inflammatory stimulus.
Maier and his colleagues (76) have repeatedly observed that
acute or chronic exposure to stressors 24 h before adminis-
tration of LPS sensitizes or primes the inflammatory re-
sponse to LPS. This priming effect is observed not only in
peripheral macrophages (112), but also in microglia iso-
lated from the hippocampus of stressed rats (75). The mi-
croglial release of high-mobility group box-1 (HMGB1), an
endogenous damage-associated molecular pattern, has been
proposed to mediate stress-induced priming via activation
of Toll-like receptor (TLR)2 and TLR4 and recruitment of
the NLRP3 inflammasome (77).
2. Autocrine/paracrine signaling by extra-adrenal
glucocorticoids
Glucocorticoids are considered to be prototypical hor-
monal factors that are produced and released into the gen-
eral circulation by the adrenal cortex to act on distant target
organs. The discovery of extra-adrenal production and re-
lease of glucocorticoids acting locally as paracrine or auto-
crine communication signals was therefore unexpected
(226). The very first organ in which extra-adrenal steroid-
ogenesis was identified was the thymus. This ran contrary to
the commonly held belief that the thymus is the main target
for glucocorticoids produced by the adrenal gland. In the
mouse, the thymus typically responds to glucocorticoids by
massive apoptosis of CD4⫹ CD8⫹ thymocytes and invo-
lution (92). However, all the elements necessary for the
local production and release of corticosterone are present in
murine thymic epithelial cells, as demonstrated in vitro
(175). Furthermore, co-culturing of thymic epithelial cells
with thymocytes induced apoptosis of thymocytes. This ef-
fect was blocked by a GR antagonist as well as by inhibitors
of the enzymes involved in the production of corticosterone.
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Thymocytes produce corticosterone in an age-dependent
manner that is concurrent with thymocyte differentiation
into CD4⫹ and CD8⫹ T cells and thymus involution (181).
Several ingenious studies have confirmed the physiological
role in vivo of the local production of glucocorticoids in the
thymus and have demonstrated their independence from
circulating glucocorticoids (226). In general, the findings of
these studies confirm that thymic-derived glucocorticoids
locally regulate thymocyte development, the rate of naive
T-cell formation, and the seeding in the periphery of recent
thymic emigrants. This function of thymic glucocorticoids
would complement the role of adrenal glucocorticoids in
regulating strong and systemic immune responses (226).
Extra-adrenal glucocorticoid synthesis has also been iden-
tified in intestinal epithelial cells that are part of the prolif-
erating cells of the crypts of the intestinal mucosa. Locally
formed glucocorticoids have both an inhibitory and a co-
stimulatory role in intestinal T-cell activation (45). On the
basis of observation that the expression of steroidogenic
genes is decreased in colon biopsies of patients with inflam-
matory bowel diseases, it has been proposed that the local
synthesis of glucocorticoids is important for controlling in-
testinal inflammation and immune responses (48).
Skin inflammation induces glucocorticoid synthesis by ker-
atinocytes. As the skin possesses all the components of a
local HPA axis, glucocorticoid synthesis in the skin can act
in a manner complementary to the HPA axis to inhibit local
inflammation and promote wound healing (257).
D. Other Hormones and Neuropeptides
After showing that human leukocyte IFN-␣ has strong an-
tigenic relatedness to adrenocorticotropic hormone
(ACTH) and endorphins (24), Smith et al. (213) demon-
strated that induction of IFN-␣ in mice by inoculation with
a noncytotoxic avian virus, the Newcastle disease virus,
simultaneously caused a time-dependent increase in corti-
costerone production by spleen lymphocytes. The culprit
turned out not to be an ACTH-like moiety of IFN-␣ but
leukocyte-derived ACTH produced by the processing of
leukocyte proopiomelanocortin in a manner similar to what
takes place in the anterior pituitary. As proopiomelanocor-
tin is at the origin of ␤-endorphin, the stage was set for a
quest for ACTH and opioid receptors and their signaling
pathways in lymphocytes (23). Classic opioid binding sites
had already been described on leukocytes (253), and it did
not take long to confirm the presence of ACTH receptors on
lymphocytes (31, 46). Other precursors of opioid peptides,
prodynorphin, which is at the origin of dynorphin and Leu-
enkephalin, and preproenkephalin, which is responsible for
Met-enkephalin and Leu-enkephalin, were found to be ex-
pressed in leukocytes of several species, together with their
receptors (68, 252). Whether opioid peptides produced by
immunocytes function as communication signals within the
483
 ROBERT DANTZER
immune system or between the immune system and the
neuroendocrine system could then be investigated.
On the basis of the observation that enkephalins promote
activity of immunocytes at baseline and suppress activity of
activated immune cells, it was proposed that these mole-
cules function as fine tuners of the immune response (68).
Evidence of immune-to-nerve communication for immune-
derived peptides was extensively described in the field of
inflammation-mediated pain. Opioid-containing immuno-
cytes migrate to the site of inflammation, where they release
␤-endorphin that activates peripheral opioid receptors on
sensory nerves to attenuate pain (38, 207, 219). The release
of opioid peptides from immune cells is mediated by several
signal molecules, including corticotrophin-releasing hor-
mone, norepinephrine, and IL-1␤, the production and re-
lease of which are upregulated at the site of inflammation
(FIGURE 2) (218).
The possibility that prolactin and growth hormone regulate
immunity by a paracrine/autocrine, rather than hormonal,
mechanism was recognized early in the study of the immune
properties of these peptides. As with other hormones, the
hormonal role of these peptides was described first. The
initial observations were made in hypophysectomized rats
in which both the deficient antibody response to sheep red
blood cells and the delayed-type hypersensitivity response
to dinitrochlorobenzene could be restored by replacement
treatment with exogenous prolactin or growth hormone
(162). This effect could be easily explained by the presence
of specific binding sites for prolactin and growth hormone
on T and B lymphocytes. Unexpectedly, the potent immu-
nosuppressive drug cyclosporine was found to increase cir-
culating levels of prolactin, and administration of the do-
pamine agonist bromocriptine blocked cyclosporine’s im-
munosuppressive properties when administered at doses
that abrogated cyclosporine-induced increase in prolactin
Local release
of endogenous
opioid peptides
Extravasation of
opioid-containing
leukocytes
– kocytes in the regulation of inflammation-
Corticotropin Sensory nerve
releasing hormone endings
+ in an amplification and prolongation of the
Fibroblasts
Inflammation
Injury
Tissue damage
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levels (43). These findings were initially interpreted to sug-
gest that hyperprolactinemia mediates the immunosuppres-
sive effects of cyclosporine. However, further studies
showed that cyclosporine and prolactin compete with each
other for binding to prolactin receptors on lymphocytes
(196) and that part of the signal reaching prolactin recep-
tors is actually a prolactin/growth hormone-related poly-
peptide produced locally by stimulated lymphocytes (103,
195).
The immunomodulatory activities of growth hormone and
prolactin have been reviewed extensively in the past 25 yr
(61, 116, 117, 236, 248), and there is no need to reiterate
this information. We know now that the production and
release of growth hormone and prolactin are regulated by
immune factors in both the pituitary gland and in lympho-
cytes, and the many different effects of these peptides on
immune cells can be explained by the intervention of post-
transcriptional and posttranslational processes generating
various isoforms and variants of these peptides (176, 246).
E. Summary
Numerous studies carried out in vitro and in vivo show that
catecholamines released by sympathetic nerve fibers have
potent modulatory effects on immune cells. Some of these
effects are mediated by alterations in monocyte and lym-
phocyte trafficking. In addition, immune cells can produce
catecholamines that act locally as paracrine or autocrine
communication factors in similar or different physiological
processes. However, the importance of this last mechanism
in immunophysiology and immunopathology has not yet
been fully appreciated. Like catecholamines, glucocortico-
ids can be produced by immune cells in lymphoid tissues
and exert local actions on different physiological processes
that are in general complementary to those mediated by
FIGURE 2. Role of opioid-containing leu-
induced pain. Proinflammatory cytokines
PAIN released by activated innate immune cells
sensitize sensory nerve endings, resulting
initial pain reaction triggered by activation
of nociceptors in response to the injury.
The pain response is downregulated by en-
dogenous opioid peptides released by lo-
cally infiltrating opioid containing leukocytes
in response to corticotropin releasing hor-
mone produced by fibroblasts. [Adapted
from Stein et al. (218).]
 NEUROIMMUNE INTERACTIONS
circulating glucocorticoids produced by the adrenal gland.
This action is not necessarily immunosuppressive as gluco-
corticoids can be proinflammatory in some conditions. The
same duality in the modality of action of other hormones
and neuropeptides is also apparent.
III. IMMUNE INFLUENCES ON THE
NERVOUS SYSTEM
A. Historical Perspective
The existence of immune influences on the nervous system
took longer to be recognized and studied than that of neu-
roendocrine influences on the immune system. The reason is
that the molecular nature of immune communication sig-
nals (monokines and interleukins, generally grouped to-
gether under the name of cytokines) was not elucidated
until the 1980s, and these molecules were just not available
for physiological studies. The first cytokine to be cloned and
produced by recombinant technology was actually a mono-
kine, IL-1. Research on cytokine actions in the brain
stemmed from two independent lines of research. The first
one was the physiology of fever, which was and still is part
of mainstream physiology. The second one was immuno-
physiology. This last line of research took longer to emerge
because of its very marginal place at the boundary between
immunology and physiology.
Fever can be defined as a regulated increase in the set point
for temperature regulation. Because the set point for tem-
perature regulation is elevated, the feverish organism gen-
erates more heat by thermogenesis and actively maintains it
by minimizing thermolysis. Fever is not caused by a direct
action of microbial pathogens on the brain thermoregula-
tory centers. It is induced by soluble factors that are
released by activated leukocytes, the so-called endoge-
nous pyrogens. The problem faced initially by fever phys-
iologists was that the molecular identity of endogenous
pyrogens could not be characterized based solely on their
in vivo pyrogenic activity, because available assays
lacked specificity. This difficulty was eventually over-
come by the development of an appropriate in vitro as-
say, the lymphocyte activating factor assay (83, 84).
Based on this assay, the first endogenous pyrogen, IL-1,
was cloned in 1984 (8, 140). Other cytokines that have
since been found to act as endogenous pyrogens include
IFN- ␣, TNF, and IL-6 (59). IL-1 represents two different
cytokines, IL-1␣ and IL-1␤, produced by two different
genes. Most of the early literature on IL-1 refers to IL-1␤.
Unless mentioned otherwise, we keep this convention in
the present review.
The understanding that immune signals could control the
immune system via a downregulating neuroendocrine feed-
back loop involving cytokine action on the brain emerged
within the context of immunophysiology. Immunophysi-
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ologists reasoned that, like any other physiological system
in the body, the immune system requires two levels of reg-
ulation: a self-regulatory process that is intrinsic to the im-
mune system, and an external regulatory loop that makes
use of the central nervous system and its means of commu-
nication with the rest of the body, i.e., the autonomic ner-
vous system and the neuroendocrine system. While main-
stream immunologists focused primarily on the self-con-
tained, self-monitored immune system, Besedovsky and
Sorkin relentlessly searched for evidence of extrinsic regu-
lation. They hypothesized that if extrinsic regulation exists,
it should make use of immune factors able to signal the
brain to recruit neuroendocrine factors with immunomodu-
latory activity. Pivotal to their research was the demonstra-
tion that the mounting of an antibody response was associ-
ated with increased activity of the HPA axis and the sym-
pathetic nervous system (18); before this discovery, the
immune response was believed to be regulated only intrin-
sically within the immune system. In mice and in rats in-
jected with sheep red blood cells (a T-cell-dependent anti-
gen), the peak of the immune response coincided with an
increase in glucocorticoid blood levels (18). In addition, this
peak was preceded by decreased norepinephrine in the
spleen that was inversely related to the magnitude of the
immune response (54). At the functional level, Besedovsky
and Sorkin showed that the glucocorticoid response to an
antigenic stimulation is required for antigenic competition.
Antigenic competition refers to the inhibition exerted by an
immune response to a first antigen relative to the immune
response to a second non-cross-reactive antigen. This form
of competition does not occur in adrenalectomized mice,
which are unable to mount a glucocorticoid response to the
first antigen (19). To search for the immunological factors
that signal the ongoing immune response to the brain neu-
roendocrine circuits, Besedovsky and Sorkin injected super-
natants of in vitro activated lymphocytes into naive mice
and identified what they called a “glucocorticoid increasing
factor” (20). In collaboration with Dinarello, who had
just cloned IL-1 and had obtained sufficient quantities of
a recombinant form of it to inject to mice, Besedovsky
and his colleagues were then able to demonstrate that this
cytokine activated the pituitary-adrenal axis in a manner
similar to the glucocorticoid increasing factor (16). Be-
cause there was still some uncertainty about the exact site
of action of IL-1 to induce glucocorticoid release, it was
important to show that this effect was mediated in the
hypothalamus, rather than in the pituitary or the adrenal
cortex (14). With this demonstration of the role of IL-1 in
a brain-mediated immunoregulatory loop, the stage was
finally set for further studies on the mechanisms of these
regulatory processes.
As we will see, studies of the influence of immune commu-
nication signals on the central nervous system followed the
same path of reasoning as the one that led to our under-
standing of the influence of neuroendocrine communication
485
 ROBERT DANTZER
signals on the immune system. The consideration of long-
range interactions between the immune system and the
brain via hormonal-like factors predominated for some
time; gradually, however, the study of short-range interac-
tions based on immune factors produced locally in the ner-
vous system gained favor.
B. Pyrogenic Effects of Cytokines
The conventional view of fever in infectious diseases
holds that the fever response is mediated by endogenous
pyrogens released by activated mononuclear phagocytes
into the general circulation. This explains why most ex-
perimental studies of fever involved intravenous injection
of endogenous pyrogens into naive experimental ani-
mals. This route of injection continued to be used even
after recombinant cytokines became available, despite
the fact that cytokines do not behave as circulating com-
munication factors.
The sequence of events leading to the production of inflam-
matory cytokines by innate immune cells in response to
pathogenic microorganisms has been identified. Specialized
monocyte/macrophage membrane receptors identified as
Toll-like receptors recognize specific molecular moieties of
pathogens called pathogen-associated molecular patterns
(PAMPs) (72, 191). Activation of Toll-like receptors by
PAMPs and by danger-associated molecular patterns
(DAMPs) that are released by damaged cells from the
host triggers a signaling cascade that culminates in the
synthesis and release of proinflammatory cytokines
(170). LPS, for instance, activates Toll-like receptor-4
(TLR4) on monocytes and macrophages. This requires
the association of LPS to a specific binding protein, LPS-
binding protein (LBP). The LPS-LBP protein complex
associates with still another membrane protein, cluster of
differentiation 14 (CD14), before recruiting another ex-
tracellular protein, myeloid differentiation factor 2 (MD-
2). Activation of TLR4 recruits two pathways, a myeloid
differentiation primary response gene 88 (MyD88)-de-
pendent pathway and a MyD88-independent pathway.
MyD88 recruits IL-1 receptor associated kinases (IRAKs)
and the adaptor molecules TNF receptor-associated fac-
tors (TRAF6) that lead to activation of both mitogen-
activated protein kinases Jun NH2-terminal kinase (JNK)
and p38, and transcription factor nuclear factor-kappaB
(NF-␬B). JNK and p38 activate, respectively, CREB and
activator protein 1 (AP1). CREB, AP1, and NF-␬B are
important for the synthesis of proinflammatory cyto-
kines. The MyD88-independent pathway recruits
TRAF3 and induces interferon-regulatory factor (IRF3)
signaling leading to expression of type I interferons and
interferon-inducible genes (170). The MyD88 pathway is
shared with other TLRs including TLR2, TLR5, and
TLR11 while the MyD88-independent pathway is shared
with TLR3.
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In terms of communication, the concept that predomi-
nated initially was that proinflammatory cytokines were
released by innate immune cells into the general circula-
tion and acted at distance. Because of their big molecular
size and their hydrophilic nature, proinflammatory cyto-
kines could not cross the blood-brain barrier. They acted
instead on those parts of the brain that are devoid of a
blood-brain barrier, the so-called circumventricular or-
gans. In the case of the fever response, the target circum-
ventricular organ was the organum vasculosum laminae
terminalis (OVLT). At the level of the OVLT, cytokines
induced the synthesis of prostaglandins E2 (PGE2). PGE2
are formed from arachidonic acid by cyclooxygenase
(COX-1 and COX-2)-dependent synthesis of prostan-
glandin H2 and further transformation by prostaglandin
synthases. PGE2 diffused inside the brain parenchyma
and activated PGE2 receptors located on thermosensitive
neurons in the anterior preoptic area of the hypothala-
mus (25). This mode of action of proinflammatory cyto-
kines was well accepted in the scientific community of
fever physiologists until further studies revealed a much
more complex circuitry than originally anticipated (70,
194, 200).
Fever in response to LPS is characterized actually by a
biphasic course. The first wave of fever originates in the
liver. It is mediated by activation of the complement cas-
cade and release of constitutive COX-1- and COX-2-
dependent PGE2 by liver macrophages (Kupffer cells)
(26). The released PGE2 activates vagal afferents that
terminate in the nucleus tractus solitarius and project to
the ventromedial part of the hypothalamus via the ven-
tral noradrenergic bundle. The second wave is mediated
by the production of inflammatory cytokines at the pe-
riphery. These cytokines induce the synthesis and release
of brain cytokines, including IL-6 which is mainly pro-
duced by astrocytes. Brain cytokines ultimately stimulate
the production and release of PGE2 by perivascular cells
and cerebral endothelial cells; this occurs mainly along
venules after induction of the PGE2 synthesizing enzymes
COX-2 and microsomal PGE synthase-1 (70, 200). Cen-
trally produced PGE2 activate PGE2 receptors 3 (EP3)
that are present on thermosensitive neurons in the me-
dian preoptic nucleus of the hypothalamus. This second
wave of fever is supported by the synthesis and release of
PGE2 by cerebral endothelial cells. The neural circuitry
activated by PGE2 acting on EP3 receptors involves two
populations of preoptic GABAergic neurons that ulti-
mately control cutaneous vasoconstriction and adipose
tissue thermogenesis via the autonomic nervous system
(200). The gradual recovery of fever is mediated by the
production of anti-inflammatory cytokines both periph-
erally and centrally (194) and by the dampening of cyto-
kine synthesis in activated macrophages under the effect
of heat stress (66, 70).
 NEUROIMMUNE INTERACTIONS
C. Activation of the Hypothalamo-Pituitary-
Adrenal Axis by Cytokines
The neuroendocrine response to an infectious agent cannot
be monitored with the same temporal precision as varia-
tions in body temperature. This certainly explains why the
response of the HPA axis to peripheral immune stimulation
is usually described as monophasic rather than multiphasic.
Nonetheless, two phases can be distinguished: an earlier
phase occurring 1–2 h after injection of LPS, and a sus-
tained response still apparent 6 h after treatment (64). Ear-
lier studies of the ACTH and corticosterone response to an
intraperitoneal injection of IL-1 revealed that these re-
sponses took longer to develop than the usual response to
an exteroceptive stressor, 2 h for the peak ACTH and cor-
ticosterone response instead of 15–30 min (16). The sus-
tained phase of the HPA axis response to LPS is dependent
on the production and release of PGE2 by the brain vascu-
lature in a COX-2- and mPGES-1-dependent manner (64).
PGE2 acts in a paracrine manner to stimulate EP1 and EP3
expressing catecholaminergic neurons in the ventrolateral
medulla of the brain (150). These neurons project to CRH
containing neurons in the paraventricular nucleus of the
hypothalamus (67). The late phase of the HPA axis is tem-
porally dependent on an inducible PGE2 synthesis interact-
ing with an earlier neuronal afferent signal involving con-
stitutive COX-1-dependent PGE2 synthesis in perivascular
cells and endothelial cells of the brain vasculature (64, 80).
The relative involvement of perivascular cells and endothe-
lial cells depends on the stimulus: IL-1 appears to activate
only perivascular cells, while LPS activates both perivascu-
lar cells and endothelial cells (206). In addition, perivascu-
lar cells exert an inhibitory effect on the response of endo-
thelial cells to LPS that becomes apparent once they are
artificially eliminated. However, this account of the role of
perivascular cells in the HPA axis response to IL-1 does not
fit with immunohistochemistry data showing a selective ex-
pression of IL-1 receptors in brain endothelial cells but not
in perivascular cells (128). Cell-specific deletion of IL-1 re-
ceptors confirms the immunohistochemistry data. Mice
lacking IL-1 receptors in hematopoietic cells including
perivascular macrophages still respond to IL-1 injected sys-
temically by increased plasma levels of ACTH and cortico-
sterone; this is no longer the case in mice lacking IL-1 re-
ceptors in brain vascular cells (151).
The possibility that LPS acts in the adrenal cortex rather
than in the hypothalamus to increase circulating corticoste-
rone levels was ruled out by studies of mice with adreno-
cortical cell-specific deletion of MyD88. This did not impair
the HPA axis response to systemic LPS, confirming the ef-
fects of LPS take place at the level of the hypothalamus or
the pituitary (113). There is evidence that cytokines, includ-
ing IL-1 and IL-2, can act directly on pituitary cells and
increase the release of various pituitary peptides, including
ACTH (15, 114). However, the relevance of this activity for
the in vivo HPA axis response to immune stimuli is still
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unclear (154), although there is evidence for direct cytokine
action on the pituitary in conditions of prolonged exposure
to cytokines after ACTH release has been initiated by CRH
(208). Folliculo-stellate cells in the anterior pituitary act as
an important source of IL-6 that influences hormonal out-
put from the anterior lobe in a paracrine manner (56, 58).
CRH-containing parvocellular neurons in the rat hypothal-
amus also produce vasopressin, which strongly potentiates
CRH-induced ACTH secretion and augments several ac-
tions of extra hypothalamic CRH in the brain. The acute
effects of IL-1 on the HPA axis are mediated predominantly
by CRH, since they are abolished by CRH immunoneutral-
ization (14). However, CRH immunoneutralization is less
effective after repeated administration of IL-1. This is due to
phenotypic changes in the expression of CRH and vasopres-
sin in hypothalamic parvocellular neurons, with vasopres-
sin dominating over CRH (230). A similar increase in vaso-
pressin stores in CRH-containing neurons occurs several
days after injection of a single dose of IL-1. This phenotypic
switch affecting CRH-containing neurons is not specific to
IL-1; it is also observed after endotoxin administration and
in response to electric foot shocks and social defeat, but not
after other types of stressors. The increased expression of
vasopressin in CRH-containing neurons is responsible for
the cross-sensitization phenomenon that can develop in re-
sponse to stressors occurring in succession: administration
of IL-1 at a given time point sensitizes the response to a
different stressor that occurs later (229).
The activating effects of cytokines on the HPA axis are
limited by the glucocorticoid resistance that develops in
response to inflammation. Glucocorticoid resistance typi-
cally occurs in humans in response to repeated injections of
IFN-␣. It takes place at the level of the hippocampus rather
than the pituitary (87). This is not an artifact due to the
administration of exogenous cytokines, since it also devel-
ops in virus-infected organisms (13, 158). Mechanisms in-
clude disruption of glucocorticoid receptor translocation
and DNA binding, and alterations in glucocorticoid recep-
tor phosphorylation status (172).
D. Behavioral Effects of Cytokines
The most visible face of the response to an infectious agent
is the sickness behavior that develops in ill individuals. In-
activity, decreased responsiveness to external stimuli, sleep-
iness, decreased appetite, and social withdrawal are the
usual signs of a microbial infection. Agitation can occur as
a prodrome, but this is rare. These behavioral alterations
are often associated with malaise and pain. They are part of
a whole repertoire of disease-control strategies that enable
organisms to adapt to the very expensive metabolic cost of
mounting an immune response and a fever (99, 100). Be-
cause behaviorists are usually not interested in the behavior
of sick individuals and physiologists rarely engage in
487
 ROBERT DANTZER
lengthy descriptions of behavioral activities, the study of
cytokine-induced sickness behavior lagged behind studies
of cytokine-induced fever and HPA axis activation. It be-
came more mainstream only after identification of the rela-
tionship between sickness behavior and symptoms of de-
pression (53).
The behavioral alterations that develop in animals injected
with LPS or cytokines recapitulate those observed in ill
individuals (37, 81). The intensity and duration of sickness
behavior can be easily measured by reduction in spontane-
ous activities such as exploration of a novel conspecific or
ambulatory activity in a familiar or novel environment
(119). Reduced appetite can be measured by decreases in
food and water intake. More elaborate indexes of sickness
behavior include decreased motivation in tasks requiring an
effort to access the reward and impaired cognitive abilities
in tasks based on recognition of a novel object, acquisition
of context-dependent fear conditioned response, and spa-
tial memory (49, 50, 156, 180).
Neal Miller was the first researcher to propose that the
changes in behavior that develop in ill individuals are the
expression of a motivational state that competes with usual
behavioral activities, rather than just a decrease in these
behaviors. He based this hypothesis on the observation that
rats injected with endotoxin were less willing to work for
food, water, and a rewarding electrical stimulation in their
lateral hypothalamus, but they were still able to increase
their response rate for gaining some rest when put into a
forced wheel-running apparatus (159). This flexibility in
the behavioral response to a stimulus depending on the
environment and the consequences of the response is typical
of a motivated behavior. Competition between the motiva-
tional state of sickness and another form of motivated be-
havior, maternal behavior, was elegantly demonstrated in
later studies carried out in lactating mice injected with LPS.
LPS-treated dams behaved in a sick way by lying immobile
and being apparently indifferent to their pups. However,
when their pups were dispersed in the cage and the nest
removed and replaced by cotton wool, dams emerged out of
their apathy and actively engaged in retrieving pups to the
cage location where the cotton wool was placed. They still
did not engage in nest building unless submitted to an am-
bient temperature of 6°C (7). The interoceptive feelings as-
sociated with sickness behavior have been studied in human
volunteers inoculated with typhoid vaccine or injected with
a small dose of LPS. Depressed mood, anhedonia, and fa-
tigue are the typical symptoms that develop in these condi-
tions (35, 63, 97, 130).
The inflammatory signals that mediate sickness behavior
are transmitted to the brain by the neural afferents that
innervate the site of the body at which the inflammatory
response takes place. When LPS is injected into the perito-
neal cavity, the vagus nerve is the predominant neural path-
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way, as demonstrated by subdiaphragmatic vagotomy ex-
periments (27) or by reversible inactivation of the dorsal
vagal complex using local injection of bupivacaine (149).
Recruitment of neural communication pathways combines
with activation of macrophage-like cells in circumventricu-
lar organs by circulating pathogen-associated molecular
patterns. This results in the local synthesis of proinflamma-
tory cytokines that slowly diffuse into the neural compart-
ment by volume diffusion while actively recruiting macro-
phages and microglia “en passant” (52, 126, 239). The
involvement of brain proinflammatory cytokines in sick-
ness behavior induced by systemic administration of cyto-
kines or LPS has been repeatedly demonstrated by blocking
experiments in which cytokine antagonists such as IL-1RA,
a specific antagonist of IL-1 type I receptor, have been ad-
ministered into the lateral ventricle of the brain in rodents
injected with cytokines or LPS at the periphery (51, 118,
127). The specific brain areas that mediate sickness behav-
ior have been difficult to delineate. There are several reasons
for this, starting with the diffuse nature of microglial acti-
vation in the brain in response to systemic inflammation, as
evidenced by positron emission tomography with ligands of
the 18-kDa translocator protein (TSPO) in monkeys and
humans injected with endotoxin (96, 198). TSPO is ex-
pressed on the outer mitochondrial membrane of microglia
and is prominently upregulated in response to inflamma-
tion. Its level of expression in resting microglia is normally
low but increases rapidly in activated microglia. This ex-
plains why imaging expression of TSPO is used as a marker
of microglial activation despite the many limitations of the
currently available TSPO radiotracers (240).
The second reason for the difficulties encountered in delin-
eating the brain areas that mediate sickness behavior is that
these brain areas differ according to the behavioral process
affected by inflammation. Decreases in food intake culmi-
nating in anorexia are unlikely to be mediated by the same
neuronal networks as fatigue or even anhedonia. Most of
the research on neuroanatomy of sickness behavior has fo-
cused on endotoxin-induced anorexia and the role of pros-
taglandins and feeding modulating peptides, including pro-
opiomelanocortin, leptin, neuropeptide Y, agouti-related
protein, and ghrelin, and their neural targets in the hypo-
thalamus (e.g., Refs. 62, 178, 200). This field of research
has expanded beyond sickness behavior because of the
somewhat paradoxical role of hypothalamic inflammation
in the resetting of energy homeostasis that is associated with
obesity (233). More in tune with the concept of sickness
behavior, decreased social interactions in rats in response to
LPS have been shown to be mediated by forebrain IL-1
acting on the central amygdala and dorsolateral bed nucleus
of the stria terminalis in a prostaglandin-independent man-
ner (127). In addition to causing social withdrawal, LPS has
aversive properties that can be evidenced using conditioned
taste aversion or conditioned place aversion (78, 247). Ac-
quisition of a conditioned place aversion in response to LPS
 NEUROIMMUNE INTERACTIONS
has been shown to be mediated by COX-1-dependent syn-
thesis of PGE2 by endothelial cells of the blood-brain bar-
rier. PGE2 acts on EP1 receptors located on dopamine D1
receptor-expressing neurons, with expression of the aver-
sion being dependent on GABA-mediated inhibition of do-
paminergic cells (78). The predominant involvement of
prostaglandins rather than brain cytokines in this behavior
is probably due to the time interval between injection of LPS
and conditioned place aversion training (10 min). This time
interval is much too short for induction of a cytokine cas-
cade in response to LPS both at the periphery and in the
brain.
Systemic inflammation caused by injection of LPS or proin-
flammatory cytokines is associated with motivational defi-
cits that can best be characterized using effort tasks, in
which animals have to exert a sustained effort to obtain an
expected reward. In mice trained to obtain a sweet milk
reward according to a progressive ratio 10 schedule (requir-
ing 1 response for the first reward, 10 for the second, 20 for
the third, and so on), administration of IL-1 decreased the
breaking point, i.e., the ratio at which mice stopped re-
sponding for the reward (131). This was not due to a de-
creased sensitivity to reward, since LPS-treated mice trained
to nose poke a switch key for a highly preferred food (choc-
olate pellets) by responding 10 times in succession and an-
other key for a less-preferred food (grain pellets) by re-
sponding only once continued to respond more on the key
giving them access to the highly preferred food than on the
key giving them access to grain pellets (237). In terms of
neurotransmitters, inflammatory stimuli have a profound
depressive effect on activity of orexin-expressing neurons
(82, 91). Orexinergic neurons are located in the perifornical
lateral hypothalamic area and regulate motivational
arousal, thanks to their widespread projections to the rest of
the brain. These neurons are inhibited by neurotensin-ex-
pressing GABAergic interneurons that sense systemic in-
flammation indirectly via alterations in leptin (91). The link
between orexin and motivation is provided by orexin-de-
pendent glutamatergic projections onto dopaminergic neu-
rons in the ventral tegmental area (28).
Despite its strong relatedness to fever, there is clear evidence
that sickness behavior is mediated by mechanisms different
from those of fever. The range of behaviorally active cyto-
kines does not fully overlap with that of pyrogens; for in-
stance, IL-6 has no behavioral effect despite its potent py-
rogenic activity and its activating effects on the HPA axis
(133). In the same manner, subdiaphragmatic vagotomy
abrogates decreases in social exploration induced by LPS
but has inconsistent effects on the fever response (141). In
addition, injections of IL-1RA into the lateral ventricle of
the brain abrogate LPS-induced decreases in social interac-
tions but have no effect on fever and activation of the HPA
axis (127).
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In summary, the effects of pathogenic microorganisms on
thermoregulation, the HPA axis, and behavior are depen-
dent on the de novo production of cytokines by activated
innate immune cells. Transmission of this peripheral im-
mune message to the brain involves multiple communica-
tion pathways with a possible relay in visceral organs such
as the liver. These communication pathways ultimately re-
cruit either other communication signals elaborated by
brain microvascular endothelial cells, e.g., prostaglandins,
or the same communication signals, e.g., IL-1, produced by
brain innate immune cells (perivascular macrophages and
micoglia). Prostaglandins are prominently involved in very
short-term responses to inflammation (⬍1 h), whereas
brain cytokines are more important for relatively longer
responses (several hours) (FIGURE 3).
E. Role of Brain Cytokines in Synaptic
Plasticity
Cytokines are not only expressed in the brain in response to
peripheral immune stimuli. They are also present constitu-
tively in the brain. Despite their expression levels being
much lower than those of their inducible counterparts, they
play an important role in synaptic physiology and plasticity.
One example is the constitutive regulation by glial TNF of
the surface expression of alpha-amino-3-hydroxy-5-meth-
yl-4-isoxazolepropionic acid (AMPA) receptors on hip-
pocampal neurons. Exposure of cultured hippocampal neu-
rons to TNF increased the levels of surface AMPA receptors
in the plasma membrane of synapses, whereas blockade of
endogenous TNF by treating cultures with a soluble form of
the TNF receptor 1 had the reverse effect (12). Similar ef-
fects were obtained in hippocampal slices. In both cases, the
influence of TNF on AMPA receptor trafficking resulted in
rapid changes in synaptic strength at glutamate excitatory
synapses. Further studies showed that these effects are spe-
cific to TNF and do not generalize to other inflammatory
cytokines (221). They are mediated by TNFR1 and phos-
phoinositol-3-kinase activation. In addition, TNF also in-
creased the endocytosis of surface GABAA receptors, result-
ing in a decrease in inhibitory synaptic transmission. The
adaptive role of TNF in the regulation of synapses varies
depending on the brain area. While cortical pyramidal cells
and motor neurons behave like hippocampal neurons in
their response to TNF, this is not the case for striatal neu-
rons. TNF drives the internalization of AMPA receptors
and reduces corticostriatal synaptic strength on GABAergic
medium spiny neurons of the dorsolateral striatum (135).
TNF acts not only on neurons but also on astrocytes. Con-
stitutive TNF is able to control glutamate release from as-
trocytes, as demonstrated by the inability of astrocytes from
TNF or TNF receptor knockout mice to release glutamate
in response to the activation of P2Y1 receptors by ATP
released during synaptic activity. Because of this deficiency,
the process of gliotransmission is impaired. The lack of
489
 ROBERT DANTZER

Brain Brain
A B Microglia Brain
PGE2s Perivascular proinflammatory
macrophages mediators
CVO
CVO

Afferent
nerves
Blood
Blood

Proinflammatory Proinflammatory
cytokines cytokines
Pathogen-associated Pathogen-associated
molecular patterns molecular patterns

Activated macrophage Activated macrophage

FIGURE 3. Immune-to-brain communication pathways. In response to pathogen-associated molecular pat-
terns such as lipopolysaccharide sensed by Toll-like receptors and the inflammasome (not represented in the
figure), activated macrophages produce and release proinflammatory cytokines in their microenvironment,
including IL-1␤ (red circles). As presented in A, proinflammatory cytokines were initially supposed to be
released in the general circulation and act at the level of circumventricular organs (CVO) where the blood-brain
barrier is fenestrated. Proinflammatory cytokines were proposed to induce there the release of lipophilic
prostaglandin E2 acting as secondary messengers on neurons. However, the demonstration that immunelike
cells in the brain including meningeal and perivascular macrophages and microglia produce and release brain
proinflammatory cytokines led to a different representation illustrated in B. The peripheral immune signal is
relayed to the brain by afferent nerves. This neural message together with slowly diffusing cytokines produced
at the level of circumventricular organs and prostaglandins produced by brain endothelial cells in response to
circulating pathogen-associated molecular patters results in the production of brain cytokines by activated
microglia. Overspill of cytokines in the general circulation can also be transported for some of them into the
brain side of the blood-brain barrier (not represented in the figure).

astrocyte-dependent activation of presynaptic N-methyl-D-
aspartate (NMDA) receptors compromises both synaptic
transmitter release and synaptic strengthening at the level of
glutamatergic synapses (199).
In contrast to what was thought originally, constitutive
TNF is produced not by neurons but by microglia. Micro-
glia are the resident macrophage population of the central
nervous system. Beyond their role as phagocytic cells in the
central nervous system when activated by injury or micro-
bial infection, microglial cells are also involved in the devel-
opment and maintenance of normal synaptic function. Like
most tissue macrophages, microglia do not originate from
blood monocytes or meningeal macrophages but from yolk
sac primitive macrophages during early development (65,
85). They persist by self-renewal in the central nervous sys-
tem until adulthood and do not need to be replenished by
peripheral cells from the circulation (86). Their differentia-
tion and maintenance are dependent on CSF-1 and IL-34
(90, 179, 243), both acting via CSF-1 receptors.
The formation of mature neural circuits requires the activ-
ity-dependent elimination or pruning of inactive synapses.
Microglia play an important role in this process, as demon-
strated by their ability to engulf synaptic material during
postnatal development in the mouse (174). They make use
of several signaling pathways for this, including the classic
complement cascade that is part of the innate immune sys-
tem. Working on the mouse reticulogeniculate system, Ste-
vens and colleagues (201, 223) demonstrated in an elegant
series of experiments that the complement protein C1q, the
initiating protein in the classical complement cascade, and
the downstream complement protein C3 localize to imma-
ture synapses and are necessary for the developmental prun-
ing of nonfunctional reticulogeniculate synapses. C1q and
C3 bind to C3 receptors that are expressed by microglia.
These receptors are upregulated in microglia during the
period of synaptic elimination and are downregulated later
on. Furthermore, C3 receptor knockout mice displayed re-
duced microglial phagocytic function and sustained deficits
in eye-specific segregation of synaptic inputs in the reticu-
logeniculate system and in synaptic connectivity (201).
What is remarkable here is the analogy of function in the
immune system and in the central nervous system: in both
systems, complement proteins clear cellular material that
has been tagged at its membrane surface for elimination
(222). In the central nervous system, this process requires a
close cooperation between synapse targets and microglia.
Microglial cells interact with neurons and synapses via sev-
eral signaling pathways other than the complement cas-
cade. One of these signaling pathways involves the chemo-
kine CX3CL1, also known as fractalkine, and its receptor
CX3CR1. Chemokines are used by hematopoietic and non-

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 NEUROIMMUNE INTERACTIONS
hematopoietic tissues to attract immune target cells by che-
motaxis. In the central nervous system, CX3CL1 is mostly
expressed by neurons and CX3CR1 is uniquely expressed
on microglial cells (5, 138). Mice lacking the fractalkine
receptor displayed a transient deficit in synaptic pruning
during the second and third postnatal weeks, together with
electrophysiological signs of synaptic abnormalities (174).
However, this was probably due to the role of the CX3CL1/
CX3CR1 signaling pathway in microglia migration into the
brain during development rather than to the involvement of
this pathway in the tagging of synapses to be eliminated,
given the reduced microglial density in the brains of
CX3CR1 knockout mice compared with littermate con-
trols.
Another signaling pathway makes use of LBP that tags syn-
apses in the developing hippocampus (245). In the innate
immune system, LBP acts as an acute phase protein and is
necessary for LPS to bind to membrane-bound CD14 on
macrophages before being able to activate TLR4 (258). LBP
is also temporarily expressed on hippocampal synapses dur-
ing development, in close association with CD14 surface
molecules present on microglia cells (245). In rodents, early
life stress in the form of daily brief pup-dam separations is
well known to cause increased anxiety-like behavior at
adulthood. Early life stress decreased the expression of syn-
aptic but not plasmatic LBP. Genetic deletion of LBP re-
sulted in increased spine density and abnormal spine mor-
phology in the hippocampus, and this was associated with
increased anxiety-like behavior at adulthood. These in-
triguing results point to a possible role for LBP in the devel-
opment and function of hippocampal synapses during the
first weeks of life (245).
F. Summary
The neuroendocrine perspective that initially dominated
studies of the neural effects of cytokines left little room for
the possibility of a local action of these molecules in the
central nervous system despite the fact that cytokines were
initially described by immunologists as autocrine and para-
crine communication factors. It is only after cytokines were
identified in the brain with their receptors that this notion
changed. Cytokines are not only induced in the central ner-
vous system in response to peripheral immune stimuli but in
addition they are expressed there constitutively and serve as
important plasticity factors in the formation and stabiliza-
tion of neuronal circuits during development.
IV. ALTERATIONS IN THE
COMMUNICATION BETWEEN THE
IMMUNE AND THE NERVOUS
SYSTEM: FROM PHYSIOLOGY TO
PATHOLOGY
Because of the bidirectional communication between the
brain and the immune system and the reliance of each of
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these systems on intercellular communication molecules
used by the other system, any alteration in one of the sys-
tems has the potential to impact the functioning of the other
system. It is beyond the scope of this review to describe all
possible instances of the reciprocal alterations in the com-
munication between the immune and the nervous system
that contribute to pathophysiology. Only two examples
will be presented to illustrate this notion, one example of a
disorder affecting the brain, major depressive disorder, and
one example of a pathology involving the immune system,
cancer. In both cases, the research agenda has been the
same: long-range communication between systems were in-
vestigated first before the possibility of short-range commu-
nication mechanisms was considered. In the context of psy-
chiatric disorders, the exact communication mechanisms
between the immune system and the brain are not yet fully
elucidated, as the research is still mainly at the description
level. In the context of stress and cancer, the attention has
shifted from long-range to short-range communication
mechanisms involving the sympathetic nervous system,
These two examples illustrate the important concept that
pathological processes develop on the basis of an intricate
network of short-range and long-range cellular and molec-
ular mechanisms of communication.
A. Major Depressive Disorder
Given that antidepressant drugs are medications that in-
crease the synaptic availability of serotonin and other
monamines in the central nervous system, depression is usu-
ally conceived of as resulting from a deficiency in these
neurotransmitter systems. However, the monoaminergic
theory of depression cannot account for all the features of
depression and its response to medication. This has led to a
reformulation of the original hypothesis. The modern neu-
robiology of depression emphasizes the role of neu-
rotrophic factors and synaptic plasticity, making depres-
sion the result of long-term alterations in synaptic strength
in brain regions that regulate mood, with brain-derived
neurotrophic factor (BDNF) as a key transducer of the ef-
fect of antidepressant drugs (165).
This brain-centric view of depression leaves little room for
mechanisms linking depression to immunity. The first stud-
ies on immune functions in depressed subjects focused on
the apparent immunosuppression in these subjects, evi-
denced by reduced proliferative responses of lymphocytes
to mitogens, decreased natural killer cell activity, and alter-
ations in numbers of several white blood cell populations
(102). However, subsequent studies revealed a much more
complex picture with signs of activation of the monocytic
and lymphocytic arms of cell-mediated immunity, charac-
terized by increased numbers of peripheral blood leuko-
cytes, monocytes, and neutrophils, and elevated circulating
levels of inflammatory cytokines and acute-phase proteins
(145). This association between depression and inflamma-
491
 ROBERT DANTZER
tion has been since confirmed by several meta-analyses (94,
104, 106). Such an association is not necessarily surprising,
in view of the likely degradation of body care and hygiene
habits that occurs in depressed subjects compared with the
general population. However, this did not discourage re-
searchers from investigating the possibility that inflamma-
tion plays a causal role in depression, given their potent
effects on sickness behavior and the similarity between
some of the symptoms of sickness and the symptoms of
depression (254). In addition, prospective epidemiological
studies confirmed that adults with high levels of circulating
IL-6 have a higher probability of developing a major depres-
sive disorder within 11–16 yr (122), and the same was true
for children aged 9 yr when examined for mental disorders
at 18 yr of age (120). In animal studies, some of the behav-
ioral alterations that develop in rodents injected with LPS
resemble the anhedonia and decreased sensitivity to reward
that are characteristic of depression. In particular, rats in-
jected with LPS displayed a reduction in preference for
food, a decrease in consumption of a saccharin solution,
and a suppression of sexual behavior. All of these responses
were alleviated by chronic but not acute treatment with
imipramine, a typical antidepressant drug (254).
Understanding about the mechanisms of inflammation-as-
sociated depression began to accrue in the late 1990s with
studies in patients with metastatic melanoma or kidney can-
cer treated with IFN-␣ and IL-2 to stimulate the immune
system and to help eliminate tumor cells that do not re-
spond to chemotherapy or radiation therapy. All patients
respond to this form of immunotherapy with sickness
symptoms, in the form of fatigue, reduced appetite, and
sleep disorders. However, one-third to one-half of patients
develop symptoms of depression within a few weeks of
treatment (40, 41). These clinical observations indicate that
depression develops on a background of immune-mediated
sickness, probably via an additional mechanism triggered
by inflammation.
Insight into this mechanism came from the observation that
the intensity of symptoms of depression is correlated with
signs of activation of the tryptophan metabolizing enzyme
indoleamine 2,3-dioxygenase (IDO) (42). IDO is an im-
mune-inducible enzyme that metabolizes tryptophan along
the kynurenine pathway and plays an important role in
immunoregulation (161). The causal involvement of this
metabolic pathway in the pathogenesis of inflammation-
induced depression was confirmed in mice injected with LPS
at a dose that activated IDO. These mice developed depres-
sion-like behavior characterized by increased immobility in
the forced-swim test and in the tail-suspension test, and
decreased sucrose preference when given the choice be-
tween a sucrose solution and tap water for drinking. Phar-
macological or genetic blockade of IDO activation abro-
gated depression-like behavior in LPS-treated mice (168).
The same effect was obtained in mice inoculated with
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Bacille Calmette-Guerin, an attenuated form of Mycobac-
terium bovis, to stimulate the immune system chronically
rather than acutely (167).
The initial hypothesis for explaining IDO’s role in inflam-
mation-induced depression was that its activation decreases
the bioavailability of tryptophan for the synthesis of the
brain neurotransmitter serotonin (53). This hypothesis had
the advantage of fitting the monoaminergic theory of de-
pression. However, a fine-grained analysis of the levels of
tryptophan, kynurenine, and kynurenine metabolites in the
blood and cerebrospinal fluid of IFN-␣-treated patients re-
vealed that tryptophan decreased only in the blood but not
in the cerebrospinal fluid, whereas kynurenine and its me-
tabolites increased in both compartments (183). These re-
sults mean that the brain can compensate for the decrease in
peripheral tryptophan levels, probably by allowing more
tryptophan to be transported into the brain by the large
amino acid transporter LAT1. Blood-brain barrier trans-
port experiments in gerbils showed that nearly all of the
kynurenine that is found in the brain in response to systemic
LPS comes from the periphery (121).
Brain kynurenine is further metabolized into neurotoxic
kynurenine metabolites by the immune-inducible enzyme
kynurenine monooxygenase, which is present in microglia.
One of these neurotoxic kynurenine metabolites is quino-
linic acid, an agonist of the NMDA receptor. When acti-
vated in response to immune stimulation, microglia also
release glutamate extrasynaptically. This release takes place
via the cystine-glutamate exchanger that regulates biosyn-
thesis of the intracellular antioxidant glutathione. In addi-
tion, astrocytes that normally uptake glutamate to recycle it
via the glutamate-glutamine cycle become much less effi-
cient for doing so in conditions of inflammation, because of
the downregulation of their high-affinity glutamate trans-
porters (89). The net result is a spillover of glutamate into
the extrasynaptic space, which, in combination with quino-
linic acid, activates extrasynaptic NMDA receptor. This
explains why blockade of NMDA receptors by ketamine is
able to abrogate the depression-like behavior induced by
LPS in mice (241). It is important to note that characteriza-
tion of this glutamatergic pathway does not discard a role
for serotonin in inflammation-induced depression. There is
evidence in particular that inflammation activates the sero-
tonin transporter, which results in a decrease in the amount
of serotonin available at the synapses (10).
During inflammation tetrahydrobiopterin is turned away
from its role as a cofactor for the hydroxylase enzymes that
catalyze the formation of 5-hydroxy-tryptophan from tryp-
tophan and tyrosine and dihydroxyphenylalanine from
phenylalanine, to be mainly consumed for the formation of
neopterin and nitric oxide by activated immune cells. This
results in a decrease in the biosynthesis of monoamines
(216).
 NEUROIMMUNE INTERACTIONS

The mechanisms of inflammation-induced depression are
summarized in FIGURE 4. From this figure it is apparent that
much has been learned about how synaptic function is af-
fected by immune mediators produced by brain immunelike
cells. Much less is known about the exact nature of the
immune-to-brain communication pathways that are ulti-
mately responsible for neuroinflammation. Recruitment of
the brain machinery is supposed to be dependent on circu-
lating factors represented either by kynurenine as a conse-
quence of peripheral IDO activation or by pathogen-asso-
ciated molecular patterns originating from the gut or other
barrier organs, especially with alterations in the microbiota
(144, 211). These circulating factors do not need to directly
reach the brain to induce depression. They can modulate the
activity of brain regions involved in the processing of emo-
tions by activating afferent autonomic nerves, as demon-
strated very elegantly by neuroimaging experiments in hu-
mans experiencing depressed mood in response to typhoid
vaccination (98).
It is not yet clear whether the mechanisms that underlie the
development of inflammation-induced depression also ac-
count for depression related to other causal factors, includ-
ing stress. The issue that still needs to be investigated is how
these neuroimmune interactions can be activated in the
brain in the absence of overt inflammation. At the clinical
level, there is evidence that even relatively minor stressors,
such as the Trier social stress test in which participants are
asked to prepare and present an impromptu speech and to
perform a difficult mental task in front of a nonresponsive,
intimating audience, can lead to the increased production of
IL-6 (190). The same elevations in circulating IL-6 are
found in individuals exposed to chronic stress. It is not
known yet whether this IL-6 derives from immune or non-
immune sources. Interestingly, stress-induced elevations in
IL-6 are higher in subjects with a history of early life stress
(44) and in subjects with low socioeconomic status (34).
The fact that these conditions are associated with chronic,
low-grade inflammation and activation of immune-to-brain
communication pathways (166) makes it very likely that
psychosocial stress-induced IL-6 is released by activated
innate immune cells, possibly via a ␤2-adrenergic-depen-
dent mechanism.
Most of the preclinical studies that address the question of
how nonimmune stressors can activate the innate immune
system rely on the social defeat paradigm, in which a resi-
dent male mouse is exposed to attacks and defeat from an
aggressor, another male mouse that is larger and trained as
a fighter. The defeat episode lasts for only a few minutes,
after which mice are typically separated to limit the extent
of wounding. Social defeat is repeated daily for several days
and in some of these experiments, the resident mouse is
forced to cohabit with its aggressor after it has been at-
tacked, although it is protected from further attacks by a
perforated divider separating the cage into two compart-

Periphery Brain

Pathogen-associated Tryptophan Inflammatory

molecular patterns mediators
IDO
+ Transport KMO
Kynurenine Quinolinic
acid
Activated
microglia
Mitochondrial
Immune-to-brain dysfunction
Toll-like receptors communication
Inflammasome pathway Glutamate

Activation of
Peripheral
innate immunity
proinflammatory NMDA glutamate Hypodopaminergic
(NF-kB
cytokines receptor activation neurotransmission
MAP kinases)

DEPRESSION

FIGURE 4. Mechanisms of inflammation-induced depression. In addition to activation of the immune-to-brain

communication pathways represented in FIGURE 3, peripheral proinflammatory cytokines activate the tryp-
tophan metabolizing enzyme indoleamine 2,3-dioxygenase (IDO) that transforms tryptophan into kynurenine.
Kynurenine produced at the periphery is transported into the brain where it is further metabolized into
neurotoxic kynurenine metabolites including quinolinic acid by another microglia-associated enzyme, kynurenine
monooxygenase (KMO). Together with glutamate released by activated microglia, quinolinic acid activates the
N-methyl-D-aspartate (NMDA) receptors. Independently of this pathway, inflammatory mediators released by
activated microglia and brain endothelial cells can also downregulate dopaminergic neurotransmission via
oxidative stress and mitochondrial dysfunction. Activation of NMDA receptors and deficient dopaminergic
neurotransmission both result in depression symptoms.

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 ROBERT DANTZER
ments. Mice exposed to repeated social defeat show social
avoidance when tested with a new male mouse and de-
creased mobility in potentially frightening environments.
Despite resembling anxiety more so than depression, these
behavioral alterations are reversed by chronic but not acute
antidepressant treatment (88). In addition, they are associ-
ated with reduced synaptic plasticity, chromatin remodel-
ing, and transcriptional activation, which also are respon-
sive to antidepressant treatment. Each defeat episode leads
to an intense activation of the HPA axis and the sympa-
thetic nervous system, and this activation is sustained by
cohabitation. Socially defeated mice show increased num-
bers of highly inflammatory and glucocorticoid-insensitive
bone marrow-derived myeloid cells in their general circula-
tion. The release of myeloid cells is mediated by activation
of ␤2-adrenergic receptors. Myeloid cells are recruited to
the brain in a chemokine-dependent manner (251). This
results in the activation of resident microglial cells and the
local production of inflammatory cytokines that negatively
affect synaptic plasticity (249). These effects could also be
mediated downstream of brain cytokines by microglial
COX-1-mediated production of PGE2 acting on EP1 recep-
tors on GABAergic neurons located in the medial prefrontal
cortex. Activation of EP1 would lead to inhibition of meso-
cortical dopaminergic neurons (227).
There are individual differences in the response to repeated
social defeat. Approximately two-thirds of the mice develop
a susceptible behavioral phenotype, whereas other mice are
resilient. Mice can be characterized as susceptible or resil-
ient on the basis of their IL-6 response to the first episode of
social defeat: those with higher circulating IL-6 levels were
more likely to be susceptible than were those with lower
IL-6 (105). This elevation in circulating IL-6 was due to a
higher number of circulating leukocytes and an increased
responsiveness to LPS stimulation. Furthermore, adoptive
transfer of bone marrow hematopoietic progenitor cells iso-
lated from susceptible mice into naive wild-type mice or
IL-6 knockout mice increased the probability of social
avoidance in the bone marrow chimera mice when they
were submitted to a subthreshold repeated social stress par-
adigm. Conversely, transfer of hematopoietic progenitor
cells from IL-6-deficient mice into naive wild-type mice de-
creased the probability of social avoidance. Both IL-6
knockout mice and wild-type mice that were administered
IL-6-neutralizing antibodies had a higher probability of re-
silience (105). These results show that leukocyte-derived
sources of IL-6 are critical in mediating the behavioral ef-
fects of repeated social stress, although it is not yet clear
how peripheral IL-6 modulates susceptibility.
Immunological memory is also affected by repeated social
defeat. The experience of repeated social defeat is associ-
ated with an augmentation of memory T-cell populations in
response to a viral infection occurring after the stress epi-
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sode (152, 153). These features are not restricted to im-
munity but extend to immune-to-brain communication.
Adoptive transfer of lymphocytes from immunocompe-
tent mice submitted to repeated social defeat into immu-
nocompromised stress-naive mice prevented the develop-
ment of anxiety-like behavior in these mice, probably by
decreasing the inflammatory response to the stress of
defeat both at the periphery and in the brain (32). This
effect was not limited to social defeat and prevention, as
adoptive transfer of lymphocytes from mice exposed to
repeated social defeat into immunocompromised mice
that had been made anxious by repeated exposure to
restraint normalized their behavior. These intriguing
findings confirm the idea that exposure to psychological
stressors could program the adaptive immune system to
confer resistance to stressors (136), but the exact mech-
anisms remain to be elucidated.
B. Cancer
The nonscientific literature is replete with anecdotal refer-
ences to the role of personality factors, repressed emotions,
and psychosocial stressors in the development of cancer.
There have been many attempts to strengthen this narrative
through experimental studies of the influence of stressors on
the proliferation and dissemination of tumor cells. The
golden age of psychoneuroimmunology has produced some
examples of this, with publications in high impact factor
journals describing the influence of the lack of control over
electric shocks on tumor growth in xenograft models of
cancer (209, 238). Current research in this field is now
decisively mechanistic and builds on our current under-
standing of tumor biology. In an elegant series of experi-
mental studies on the effect of repeated immobilization
stress on the progression and dissemination of cancer in
murine models of solid epithelial tumors, oncologists col-
laborating with psychologists have clearly demonstrated a
definitive role for activation of the sympathetic nervous
system in modifying the tumor microenvironment and the
immune response to the tumor (FIGURE 5) (4, 47, 109, 132,
210, 228).
Not surprisingly, most of these effects are mediated by ␤2-
adrenergic activation of multiple local intracellular signal-
ing pathways involving protein kinases, CREB, EPAC, and
MAPK. The net results include inhibition of DNA damage
repair and p53-associated apoptosis, activation of onco-
genic signaling pathways, increased inflammation by en-
hanced expression of proinflammatory cytokines, recruit-
ment of macrophages into the tumor parenchyma, produc-
tion of tumor growth factors (including transforming
growth factor-␤, vascular endothelial growth factor, and
matrix metalloproteases), activation of mesenchymal cells
present in tumor stroma, promotion of angiogenesis, inhi-
bition of anoikis, and increased resistance to chemotherapy.
In addition, activation of sympathetic nervous system sig-
 NEUROIMMUNE INTERACTIONS

BRAIN

ACTH Sympathetic
efferents

Adrenal gland Spleen and lymphoid tissue Liver Adipose tissue

Myeloid Insulin Adipokines

Cortisol progenitors Glucose resistance Inflammation

TUMOR MICROENVIRONMENT

Immune cells & fibroblasts Tumor cells Tumor metabolism Vascular endothelial cells
Myeloid derived suppressor cells Oncogene activation Aerobic glycolysis/ Angiogenesis
Cytotoxicity NK cells EMT oxidative phosphorylation Prostaglandins E2
Cellular immune response Apoptosis inhibition HIF-1α
Macrophage recruitment & DNA repair inhibition PI3K/AKT, PKM2
inflammation MMP2, MMP9

FIGURE 5. Mechanism of stress-induced tumor progression and dissemination. Stress facilitates the devel-
opment of immunotolerance by activation of the hypothalamic pituitary adrenal axis which results in decreased
cytotoxicity of natural killer cells (NK cells) and reduced cellular immune responses to the tumor antigens. At
the same time, activation of the sympathetic nervous system induces profound alterations in tumor cells and
in the tumor microenvironment both directly by sympathetic nerve endings innervating the organ in which the
tumor develops and indirectly via the liver and adipose tissue. Red arrows represent communication via the
general circulation, dashed blue arrows represent communications via nerves, and blue arrows represent
communication within the tumor microenvironment. NK, natural killer; EMT, epithelial-to-mesenchymal trans-
lation of cancer cells; DNA, deoxyribonucleic acid; MMP, matrix metalloproteinase; HIF-1␣, hypoxia inducible
factor-1␣; PI3/AKT, phosphatidylinositol 3-kinase/protein kinase B signaling pathway; PKM2, M2 isoform of
pyruvate kinase. [Adapted from Cole et al. (47).]

naling contributes to the escape of tumors from immuno-
surveillance by inhibiting type I and II interferon signaling
and by suppressing the cytotoxic function of T lymphocytes
and natural killer cells.
Nerves innervating solid tumors and their microenviron-
ment mediate the influences of stress on tumor progression
and dissemination. Female mice with orthotopic or sponta-
neous mammary tumors responded to restraint stress by
increased turnover of norepinephrine in sympathetic nerves
innervating the tumor (225). The peripheral nerves that
innervate the tumor are not restricted to those preexisting in
the tissue in which the tumor develops: tumor cells can
actually promote neurogenesis. In two murine models of
cancer, including an orthotopic xenograft model of human
prostate cancer cells in nude mice and a genetic model of
prostate cancer in immunocompetent mice, tumor growth
was associated with infiltration of autonomic nerve fibers
into the tumor mass. Chemical or surgical sympathectomy
as well as genetic deletion of ␤2-adrenergic receptors pre-
vented the early phase of tumor development. Pharmaco-
logical blockade or genetic disruption of the stromal type 1
muscarinic receptor abrogated tumor dissemination (146).
Similar results have been obtained in a mouse model of
gastric cancer (256). Sensory neurons can also play a role,
as demonstrated by the slower initiation and progression of
cancer after sensory neuron ablation by neonatal injection
of capsaicin in a model of pancreatic ductal adenocarci-
noma (197).
In general, the notion that the peripheral nervous system
is able to adapt to an ongoing disease process and con-

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 ROBERT DANTZER

tribute to its evolution is not totally new. For instance, C. Summary

complex interactions between neurons, glial cells, im-
mune cells, and endocrine cells have been shown to take
place during pancreatitis. They modulate inflammation
and cancer growth, while at the same time undergoing
plastic changes in the proportion of autonomic and sen-
sory fibers innervating the affected organ and in the
quantity of mediators they release. This form of neural
plasticity has been well studied in pancreatitis and its
progression to pancreatic cancer (55). The outgrowth of
nerves in solid tumors is driven by the production of
neurotrophic factors, such as nerve growth factor (NGF),
by cancer cells (111). Knocking down NGF or its recep-
tors, or administering an NGF receptor inhibitor, atten-
uated the proliferation and migration of pancreatic can-
cer cells in vitro (11). This dependence on neurotrophins
could account for the perineural invasion that character-
izes tumor metastasis in several solid malignancies, such
as head and neck squamous cell carcinoma (189).
We have restricted ourselves to only two examples to illus-
trate the possibility that pathological processes develop on
the basis of an intricate network of short- and long-range
cellular and molecular mechanisms of communication.
These examples are not the only ones, and there are many
other instances of altered communication mechanisms be-
tween the immune system and the nervous system in the
pathophysiology of many disorders. This intricacy explains
at least in part the important psychological comorbidity of
physical illness and provides some clues as to how to better
treat these disorders.
V. CONCLUSIONS AND PERSPECTIVES
In the earlier ages of psychoneuroimmunology, Blalock (21)
proposed that the immune system may function as a diffuse
sensory organ specialized in the detection of the nonself in a
manner complementary to that employed by classic sensory

A B
Central nervous Central nervous system
system Local molecular interactions
between neural cells and
resident immune-like cells

Sympathetic
nervous
system
Neuroendocrine Neuroendocrine system
system Local molecular interactions
between neuroendocrine cells and
resident immune-like cells

Vasculature of
lymphoid organs
-> trafficking of immune cells Neural
afferents

Immune Immune cells

system Local interactions between immune
mediators and neuroendocrine
mediators produced by immune cells

FIGURE 6. Schematic representation of neuroimmune interactions. A: the initial notion that neuroimmune
interactions take place via mediators released in the general circulation by the neuroendocrine system. B:
summary of the knowledge presented in this review showing that long-distance communication between the
central nervous system and the immune system takes place mainly via neural pathways and much less so via
circulating neuroendocrine factors. Long-distance communication via neural pathways is bidirectional, from the
central nervous system to the immune system and vice versa. Long-distance communication pathways
modulate the functioning of local or short-range communication pathways that involve intricate interactions
between resident immunelike cells (mainly microglia and astrocytes, but also endothelial cells) and neuronal
cells in the nervous system, and between immune mediators and neuroendocrine mediators produced locally
by immune cells in the immune system in addition to mediators released locally by nerve endings. The immune
phenotype of the microenvironment of the affected organ can be modified by alterations in immune cell
trafficking induced by noradrenergic or more rarely cholinergic modulation (not represented in the figure) of the
vasculature of lymphoid organs. This is more likely to take place at the periphery than in the nervous system
that is protected by the blood-brain barrier even if it can become leaky in some conditions. Blue arrows
correspond to neural communication pathways and red arrows to humoral communication pathways.

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 NEUROIMMUNE INTERACTIONS
organs. He speculated that “in the future, it may be difficult
to distinguish the receptors and signals that these systems
use for communication within and between one another.”
Because of the reluctance of the scientific community to
accept this concept despite the convincing examples of com-
munication Blalock provided, the original review paper he
submitted was ultimately published as an opinion piece.
This reluctance was still apparent a few years later, when
the first review paper on the neuroimmune mechanisms of
sickness behavior was submitted (119).
Thanks to the research work that has been carried out since
then, the situation has changed considerably. It is now fully
recognized that the nervous system and the immune system
do not function independently from one another, but that
the central nervous system utilizes cellular and molecular
elements of immune communication for its own purposes,
while the immune response is regulated in part by neuroen-
docrine mediators produced by immunocytes (FIGURE 6).
The intricate interactions between these two systems play a
key role in health and disease. Several examples of this
necessary communication between immune cells and neu-
ronal cells have been provided in this review, and their
implications for pathology have been discussed. Not only
does the immune system have a considerable impact on
neural functions, but conversely the somatosensory and au-
tonomic nervous systems play an active role in the coordi-
nation of the organism’s defense to infection and injury via
positive and negative modulation of immune responses. Pa-
thology can emerge either from the dysfunction of one of
these interacting systems or from the deflection of the mo-
lecular or cellular mechanisms specifically involved in their
reciprocal regulation.
It is generally agreed that the knowledge gained from these
studies will help to clarify pathophysiology and inform fu-
ture therapeutics, thanks to the emergence of new targets.
For example, who would have thought a few years ago that
it would be possible to treat depression with the TNF an-
tagonist infliximab, at least in patients with low-grade
chronic inflammation (184), or that the use of beta-blockers
could prolong overall survival in patients with ovarian can-
cer (244)? Nonetheless, adding such approaches to the ther-
apeutic horizon will require detailed investigation into
which patients will likely benefit from them and at what
time point in the course of the disease they are more likely to
succeed.
Concerning this last aspect, it is important to note that we
still know very little, if anything at all, about the temporal
aspect of neuroimmune interactions. As just one example, a
recent study demonstrated that, although the neuropathic
pain induced by chemotherapeutic agents such as paclitaxel
is mediated at the very early stage of its development by
activation of the innate immune system, its resolution is
actually dependent on the involvement of the adaptive im-
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mune system and more specifically the trafficking of CD8⫹
T cells into the dorsal root ganglia (129). This means that a
treatment targeting the immune system could actually be
detrimental when given at the wrong time point in the dis-
ease process.
ACKNOWLEDGMENTS
Address for reprint requests and other correspondence: R.
Dantzer, Dept. of Symptom Research, Univ. of Texas MD
Anderson Cancer Center, Houston, TX 77005 (e-mail:
rdantzer@mdanderson.org).
GRANTS
This work was supported by National Cancer Institute
Grants R01CA193522 and CA183736, National Institute
of Mental Health Grant R21MH104694, and National In-
stitute of Neurological Disorders and Stroke Grant
R01NS073939.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared
by the author.
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