Cytokine Actions in the Brain:
From Sickness Behavior to
Depression
Robert Dantzer
Integrative Immunology & Behavior Program
University of Illinois at Urbana-Champaign
(dantzer@uiuc.edu)
The Golden Age of Psychoneuroimmunology in the 1970s:
Immune Responses are Modulated by Brain Events
What is processed by the brain has an impact on the functioning of the
immune system (e.g., psychosocial events, emotions…).
This is possible because the immune system is connected to the brain via
autonomic nerves and neuroendocrine factors and shares common cellular
communication messengers.
CNS
STRESSORS
Neuroendocrine
factors
ANS
Immune cells
An Emerging Concept in the late 1980s:
The Immune System Needs to Talk to the Brain
Like any other physiological system in the body, the immune system needs
the brain to do what it has to do and to be regulated
If it is the case, the brain has an « immunostat » that enables it to
perceive and represent what is going on in the immune system, using
immune cell communication molecules (cytokines)
CNS
ANS &
Neuroendocrine Factors
Cytokines
Immune cells
Pathogen-associated
molecular patterns
(PAMPs)
Innate immune
cells (TLRs)
NFkB
Proinflammatory
cytokines
Interleukin-1b
Peripheral immune
response
- non-specific
- specific
CNS response
- fever
- HPA axis activation
- sickness behavior
- malaise
SICKNESS BEHAVIOR
NT
CRH/AVP
ACTH
+
Adrenal cortex
Cortisol
Efferent
vagus
-
Proinflammatory cytokines
(IL-1, TNFa, IL-6)
Innate immune cells
-
PAMPs
The syndrome of just being sick
In 1925, Hans Selye who was then a second year medical
student at Prague noted that irrespective of their disease all
patients “felt and looked ill, had a coated tongue, complained of
more or less diffuse aches and pains in joints, and of intestinal
disturbances associated with loss of appetite”. They also
generally “had fever, enlarged spleen or liver, inflamed tonsils,
and a number of other general symptoms.”
He called this condition the syndrome of just being sick.
1.What are the mechanisms of action of
cytokines on the brain?
2. How is organized the sickness response to
cytokines?
3. How does sickness behavior translate into
pathology?
The sickness inducing effects of peripheral IL-1 are
mediated centrally (from Kent et al, 1992)
IL-1b
IL-1ra
How can peripherally produced cytokines
act in the brain?
PAMPs
Peripheral
cytokines
Brain targets
HPA axis
activation
Fever
Sickness
behavior
Peripheral cytokines do not need to get into the
brain because they are produced in the brain
PAMPs
Humoral pathway
Peripheral
cytokines
Brain
cytokines
Neural pathway
PGE2
Brain targets
HPA axis
activation
Fever
Sickness
behaviour
Visualization of IL-1 Receptors via NFkB Activation
in the Rat Brain (Nadjar et al., 2003-2005)
IL-1b ir
NFkB ir
AP
1-2 h
BV
NTS
2-4 h
IL-1b
Vagotomy abrogates the induction of hypothalamic
IL-1b expression and sickness behavior
LPS/ IL-1
Hypothalamic expression of IL-1b
Social exploration
VGX
Sham
From Layé, Bluthe et al, 1995
Conclusions
By their actions on the brain, proinflammatory cytokines
produced by activated macrophages and monocytes induce
sickness behavior
The brain forms a molecular and cellular representation of the
peripheral immune response
This representation is mediated by several immune-to-brain
communication pathways including a neural pathway that is
critical for sickness behavior
1. Why do we feel and behave in a sick way when
we are ill?
2.How is organized the sickness response to
cytokines?
3. How does sickness behavior translate into
pathology?
The behavioral effects of cytokines correspond to
a reorganization of the host’s priorities (Aubert et al., 1997)
Medical interpretation
Internal state
(weakness)
Cytokines
Behavioral
alterations
Motivational interpretation
Cytokines
Internal
state
Environmental
contingencies
LPS
24°C
24°C
Behavioral
alterations
LPS
6°C
MOTIVATIONAL INTERPRETATION OF FEAR
Threat
Fear
Fear feelings
Fear behavior
Visceral arousal
MOTIVATIONAL INTERPRETATION OF SICKNESS
Threat
Fear
Fear feelings
Fear behavior
Visceral arousal
Pathogenic
microorganisms
Sickness
Malaise
Sickness behavior
Visceral arousal
The brain forms a representation of the
peripheral innate immune response. This
representation is at the origin of sickness
behavior
Sickness behavior corresponds to a
reorganization of the host’s priorities.
Sickness behavior is normally fully reversible
Georges Canguilhem: « être en bonne santé, c’est pouvoir
tomber malade et s’en relever » (To be healthy is to be
able to become ill and recover from it…)
1. Why do we feel and behave in a sick way when
we are ill?
2. How is organized the sickness response to
cytokines?
3.How does sickness behavior translate into
pathology?
Pathogen-associated
molecular patterns
Endogenous danger signals
Peripheral proinflammatory cytokines
Anti-inflammatory
cytokines
Cortisol
Brain proinflammatory cytokines
AVP
a-MSH
Non specific symptoms of disease
Anorexia
Anhedonia
Cachexia
Pain
Cognitive disorders
Mood disorders
Fatigue
What does happen when the innate immune system
remains activated?
Examples :
- Chronic inflammatory disorders
- Chronic administration of exogenous cytokines
- Cancer
- Aging
- Viral pathologies
Each of these conditions is associated not
specific signs of the disease but also
specific symptoms of an exaggerated
response such as fatigue and an increased
of affective and cognitive disorders.
only with
with non
sickness
incidence
Prevalence of Depression in Patients with
Immune-based Disorders
Condition
Prevalence
 General Population
 Cancer
 Autoimmune Disorders
 Cardiovascular Disease
 Chronic illnesses (e.g. irritable bowel
syndrome, chronic fatigue syndrome)
 Obesity / Metabolic Syndrome
See for review, Evans et al., Biological Psychiatry, 58, 2005
5-10%
18-39%
15-40%
15-40%
15-60%
20-30%
Symptom Intensity
Temporal Evolution of the Behavioral Symptoms
Induced by Chronic Cytokine Therapy
Neurovegetative Symptoms
(e.g., fatigue)
Mood and Cognitive
Symptoms
Sickness Behavior
Depression
Minimally responsive
to antidepressants
W 1-4
responsive
to antidepressants
W 4-8
Time on IFN-Alpha
W 8-12
Initial MADRS Scores Predict
Depressive Symptoms Four Weeks Later
MADRS Score (D26)
35
R=0.753
p<0.001
30
25
20
IL-2
15
IL-2+IFN
10
Iv IFN
5
Y=1,53X+4,25 p<0,001
0
0
2
4
6
8
10
12
MADRS Score (D0)
Capuron et al., NEJM,1999; 340: 1370
Pituitary-adrenal response to IFNa predicts the
occurrence of depressive symptoms
ACTH
800
Cortisol
700
***
600
30
***
*
25
***
400
300
**
100
*
**
20
15
10
**
200
CORT (g/dl)
pg/ml
500
*
***
35
#
5
0
0
0h
1h
2h
3h
IFN
Depressed patients (n=8)
Non- depressed patients (n=8)
0h
1h
2h
3h
IFN
Capuron et al., Am J Psychiat, 2003.
Depressed mood is
specifically associated
with decreased plasma
tryptophan levels in
IFNa-treated patients
Tryptophan
Non-depr
MDD
MADRS score
30 R=-0.50
p<0.05
25
20
Symptom dimensions
15
Depression
Anxiety
Cognitive
Neurovegetative
Somatic
10
5
0
-60 -40 -20
0
 TRP
20
40
rTRP
-0.627*
-0.674**
-0.636**
-0.381
-0.220
** p<0.01
Capuron et al., 2002, 2003
Immune stimuli activate a key enzyme
in the metabolism of tryptophan
Food
Proteins
Tryptophan
5-HTP
Kynurenine
5-HT
IDO
IFNg
PAMPs
Quinolinic acid
Alterated
glutamatergic
neurotransmission
Decreased
serotoninergic
neurotransmission
IDO = indoleamine 2,3 dioxygenase
BLOCKADE OF PROINFLAMMATORY CYTOKINE EXPRESSION BY
Forced Swim
Test
FST Immobility (s)
MINOCYCLINE ABROGATES LPS-INDUCED DEPRESSIVE-LIKE BEHAVIOR
**
160
120
80
40
Sal
Mino
**
TST Immobility (s)
Tail Suspension
Test
Sal
LPS
300
200
100
Sal
Mino
0
Sal
LPS
BLOCKADE OF IDO BY 1-METHYL-TRYPTOPHAN ABROGATES
FST Immobility (s)
LPS-INDUCED DEPRESSIVE-LIKE BEHAVIOR
*
160
120
Saline
80
LPS
40
Placebo
1-MT
TST Immobility (s)
*
300
200
100
Placebo
1-MT
0
Saline
LPS
Proinflammatory
cytokines
0 .4
0 .3
0 .2
0 .1
LPS
Age
B
IL-6 (ng/ml)
24
Proinflammatory
cytokines
40
30
20
10
6
– –
6 m 24 m
*
12
LPS
Age
50
6 m 24 m
18
*
60
0
– –
80
*
60
40
20
0
0
Anti-inflammatory
cytokines
70
0 .0
Anti-inflammatory
cytokines
Aging
*
IL-10 (ng/ml)
0 .5
IL-10 (ng/ml)
Adult age
A
IL-6 (ng/ml)
Aging is associated with
chronic brain inflammation
+ +
6 m 24 m
+ +
6 m 24 m
Figure 7. Secretion of IL-6 and IL-10 by
glia from adult and aged mice in the
absence (A) or presence (B) of 20 ng/mL
of LPS. Bars represent the mean ± SEM.
*P<.05.
(Johnson et al., 2003)
and this chronic brain inflammation
has functional consequences…
20
20
20
00
0
20
-20
-20
40
-40
-40
60
-60
*
-60 * *
80 **
-80
-80 *
100
-100
-100** **
* *
22 44
2 4
Duration of Immobility (sec)
Adult CON
CON Aged
Aged CON
CON
Adult
AdultLPS
CON Aged
AgedLPS
CON
Adult
Adult
LPS
Aged LPS
Adult LPS
Aged LPS
Forced swim test
A.
180 24 h
b
**
*
140
120
*,
‡‡
*,
*,‡
88
8
24
24
24
Hours
Post
Injection
Hours
HoursPost
PostInjection
Injection
(Godbout et al.)
a
100
80
60
a
40
20
Adu lt Adu lt Ag ed Ag ed
Salin e L P S Salin e L P S
. 140
B.
*,
‡‡
*,
*,‡
b
160
0
Duration of Immobility (sec)
baseline)
(%
Behavior
Social
baseline)
(%
Behavior
Social
Social Behavior (% baseline)
Social exploration
72 h
120
a
100
80
b
a
a
60
40
20
0
Adu lt Adu lt Ag ed Ag ed
Salin e L P S Salin e L P S
The brain forms a molecular and cellular
representation of the activation state of the
innate immune system.
This representation organizes the normal response
of the host to infection and danger signals.
This representation can lead to the development
of disorders of affect and cognition.
These processes are amplified in situation of
chronic inflammation including aging & obesity.
Neuroimmune interactions represent new
targets for health promoting compounds.
Chronic peripheral
inflammation
Risk factors for
inflammatory disorders
Activation of
brain cytokine
signaling
Risk factors for
psychiatric disorders
Subjective health complaints:
- Fatigue, Pain
- Sleep disorders
- Depressed mood
- Cognitive alterations
INVESTIGATIONS IN
NEURO-IMMUNE PROGRAMMING
Neonatal activation of the immune system
(Variation factors: time, nature of the stimulus}
Alterations in BW regulation
adiposity, fever, HPA axis
activity and reactivity
Neural development
Anxiety
Neurodevelopmental hypothesis of
autism and schizophrenia