Cytokine Actions in the Brain: From Sickness

Behavior to Depression

Robert DantzerIntegrative Immunology & Behavior

ProgramUniversity of Illinois at Urbana-

Champaign(dantzer@uiuc.edu)

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

Immune cells

The Golden Age of Psychoneuroimmunology in the 1970s:

Immune Responses are Modulated by Brain Events

ANSNeuroendocrine

factors

STRESSORS

CNS

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)

ANS &Neuroendocrine Factors

Cytokines

CNS responseCNS response - fever- fever - HPA axis activation- HPA axis activation - sickness behavior- sickness behavior - malaise- malaise

PeripPeripheral heral immune responseimmune response - non- non--spspecificecific - sp- specificecific

Interleukin-1

ProinfProinflammatory lammatory cytokinescytokines

Pathogen-Pathogen-associated associated

molecular patternsmolecular patterns(PAMPs)(PAMPs)

Innate Innate immune cells immune cells

(TLRs)(TLRs)NFB

PAMPPAMPss

++

ACTHACTH

Innate immune cellsInnate immune cells

CortisolCortisol

NTCRH/AVP

Adrenal cortexAdrenal cortex

--

Efferentvagus

--

Proinflammatory cytokines(IL-1, TNF, IL-6)

SICKNESS BEHAVIOR

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-1 IL-1ra

How can peripherally produced cytokines act in the brain?

Peripheralcytokines

Brain targets

HPA axis Fever Sicknessactivation behavior

PAMPs

Peripheral cytokines do not need to get into the brain because they are produced in the

brain

Peripheralcytokines

Brain targets

HPA axis Fever Sicknessactivation behaviour

PAMPs

Braincytokines

Humoral pathway

Neural pathway

PGE2

Visualization of IL-1 Receptors via NFB Activation

in the Rat Brain (Nadjar et al., 2003-2005)

IL-1

AP

NTS

NFB irIL-1 ir

BV1-2 h

2-4 h

Vagotomy abrogates the induction of hypothalamic IL-1 expression and sickness

behavior

From Layé, Bluthe et al, 1995

VGX

Sham

LPS/ IL-1 Hypothalamic expression of IL-1 Social exploration

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

Conclusions

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 toThe behavioral effects of cytokines correspond toa reorganization of the host’s priorities (Aubert et al., 1997)a reorganization of the host’s priorities (Aubert et al., 1997)

Motivational interpretationMotivational interpretation

CytokinesCytokines Internal stateInternal state(weakness)(weakness)

BehavioralBehavioralalterationsalterations

CytokinesCytokines InternaInternallstatestate

BehavioralBehavioralalterationsalterations

24°C24°C

LPSLPS

24°C24°C 6°C6°C

LPSLPS

EnvironmentalEnvironmental

contingenciescontingencies

Medical interpretationMedical interpretation

MOTIVATIONAL INTERPRETATION OF FEAR

FearThreat Fear feelings

Fear behavior

Visceral

arousal

MOTIVATIONAL INTERPRETATION OF SICKNESS

Pathogenicmicro-

organismsSickness

FearThreat

Malaise

Sickness

behavior

Visceral arousal

Fear feelings

Fear 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 reversibleGeorges 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?

Peripheral proinflammatory cytokinesAnti-inflammatory

cytokinesCortisol

AVP-MSH

Pathogen-associatedmolecular patterns

Endogenous danger signals

Brain proinflammatory cytokines

Anorexia AnhedoniaCachexia

Fatigue

Non specific symptoms of disease

PainCognitive disordersMood disorders

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 only with specific signs of the disease but also with non specific symptoms of an exaggerated sickness response such as fatigue and an increased incidence of affective and cognitive disorders.

Prevalence of Depression in Patients with

Immune-based Disorders

General Population Cancer Autoimmune Disorders Cardiovascular Disease Chronic illnesses (e.g. irritable bowel

syndrome, chronic fatigue syndrome) Obesity / Metabolic Syndrome

5-10% 18-39% 15-40% 15-40% 15-60%

20-30%

Condition Prevalence

See for review, Evans et al., Biological Psychiatry, 58, 2005

Temporal Evolution of the Behavioral Symptoms Induced by Chronic Cytokine

Therapy

Neurovegetative Symptoms(e.g., fatigue)

Sickness Behavior

Mood and CognitiveSymptoms

Depression

Sym

pto

m In

ten

sity

Time on IFN-Alpha

W 1-4 W 4-8 W 8-12

Minimally responsive to antidepressants

responsive to antidepressants

Initial MADRS Scores PredictInitial MADRS Scores PredictDepressiveDepressive Symptoms Four Weeks LaterSymptoms Four Weeks Later

MADRS Score (D0)MADRS Score (D0)

Iv IFN

IL-2+IFN

IL-2

00 22 44 66 88 1010 121200

55

1010

1515

2020

2525

3030

3535

MA

DR

S S

core

(D

26)

MA

DR

S S

core

(D

26) R=0.753R=0.753

p<0.001p<0.001

Y=1,53X+4,25 p<0,001Y=1,53X+4,25 p<0,001

Capuron et al., NEJM,1999; 340: 1370

IFN

0h 1h 2h 3h

pg/m

l

0

100

200

300

400

500

600

700

800

**

****

***

**

#

0h 1h 2h 3hC

OR

T (g

/dl)

0

5

10

15

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25

30

35

**

****

****

ACTHACTH CortisolCortisol

Pituitary-adrenal response to IFNPituitary-adrenal response to IFN predicts the predicts the occurrence of depressive occurrence of depressive symptoms

Depressed patients (n=8)Depressed patients (n=8) Non- depressed patients (n=8)Non- depressed patients (n=8) Capuron et al., Am J Psychiat, 2003.

IFN

Capuron et al., 2002, 2003

Tryptophan

** p<0.01** p<0.01

Non-depr

MDD

Symptom dimensionsSymptom dimensions rTRP rTRP

DepressionDepression -0.627*-0.627*AnxietyAnxiety -0.674**-0.674**CognitiveCognitive -0.636**-0.636**NeurovegetativeNeurovegetative -0.381-0.381SomaticSomatic -0.220-0.220

TRP

-60 -40 -20 0 20 40

MA

DR

S s

core

0

5

10

15

20

25

30 R=-0.50p<0.05

Depressed mood is specifically

associated with decreased plasma

tryptophan levels in IFN-treated patients

Food Proteins

Tryptophan

Immune stimuli activate a key enzyme

in the metabolism of tryptophan

5-HTP

5-HT

Decreasedserotoninergic

neurotransmissionAlteratedglutamatergic

neurotransmission

Kynurenine

Quinolinic acid

IDO

PAMPs

IFN

IDO = indoleamine 2,3 dioxygenase

BLOCKADE OF PROINFLAMMATORY CYTOKINE EXPRESSION BY

MINOCYCLINE ABROGATES LPS-INDUCED DEPRESSIVE-LIKE BEHAVIOR

40

80

120

160

MinoSal

FS

T I

mm

ob

ilit

y (

s)

SalLPS

**

SalLPS

0

100

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TS

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mm

ob

ilit

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s)

MinoSal

**

Forced SwimTest

Tail SuspensionTest

BLOCKADE OF IDO BY 1-METHYL-TRYPTOPHAN ABROGATES

LPS-INDUCED DEPRESSIVE-LIKE BEHAVIOR

Saline

LPS40

80

120

160

FS

T I

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ob

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s)

1-MTPlacebo

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1-MTPlacebo

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LPS

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IL-6

(ng

/ml)

IL-1

0 (n

g/m

l)

AgeLPS

6 m 24 m– –

**A

6 m 24 m– –

0

6

1 2

1 8

2 4

0

2 0

4 0

6 0

8 0

IL-6

(ng

/ml)

IL-1

0 (n

g/m

l)

AgeLPS

6 m 24 m+ +

**B

6 m 24 m+ +

Figure 7. Secretion of IL-6 and IL-10 byglia from adult and aged mice in the absence (A) or presence (B) of 20 ng/mLof LPS. Bars represent the mean ± SEM.*P<.05.

0

1 0

2 0

3 0

4 0

5 0

6 0

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0 .0

0 .1

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0 .5

IL-6

(ng

/ml)

IL-1

0 (n

g/m

l)

AgeLPS

6 m 24 m– –

**A

6 m 24 m– –

0

6

1 2

1 8

2 4

0

2 0

4 0

6 0

8 0

IL-6

(ng

/ml)

IL-1

0 (n

g/m

l)

AgeLPS

6 m 24 m+ +

**B

6 m 24 m+ +

Figure 7. Secretion of IL-6 and IL-10 byglia from adult and aged mice in the absence (A) or presence (B) of 20 ng/mLof LPS. Bars represent the mean ± SEM.*P<.05.

Proinflammatorycytokines

Anti-inflammatory

cytokines

Adult age

Proinflammatorycytokines

Anti-inflammatory

cytokines

Aging

(Johnson et al., 2003)

Aging is associated withchronic brain inflammation

and this chronic brain inflammation has functional consequences…

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Social exploration

(Godbout et al.)

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Forced swim test 24 h

‡‡‡‡‡‡

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

Activation of brain cytokine

signalingRisk factors for

inflammatory disordersRisk factors for

psychiatric disorders

Subjective health complaints:- Fatigue, Pain- Sleep disorders- Depressed mood- Cognitive alterations

INVESTIGATIONS INNEURO-IMMUNE PROGRAMMING

Neural development

Neurodevelopmental hypothesis of autism and

schizophrenia

Neonatal activation of the immune system

Alterations in BW regulationadiposity, fever, HPA axis activity and reactivity

Anxiety

(Variation factors: time, nature of the stimulus}