1 / 35

Cytokine Actions in the Brain: From Sickness Behavior to Depression Robert Dantzer

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). CNS. The Golden Age of Psychoneuroimmunology in the 1970s:

lars
Download Presentation

Cytokine Actions in the Brain: From Sickness Behavior to Depression Robert Dantzer

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. 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)

  2. CNS 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. STRESSORS Neuroendocrine factors ANS Immune cells

  3. CNS 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 Immune cells

  4. Peripheral immune response - non-specific - specific CNS response - fever - HPA axis activation - sickness behavior - malaise Pathogen-associated molecular patterns (PAMPs) Innate immune cells (TLRs) NFkB Proinflammatory cytokines Interleukin-1b

  5. SICKNESS BEHAVIOR NT CRH/AVP Proinflammatory cytokines (IL-1, TNFa, IL-6) ACTH Efferent vagus + Adrenal cortex Innate immune cells - - Cortisol PAMPs

  6. 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.

  7. What are the mechanisms of action of cytokines on the brain? • How is organized the sickness response to cytokines? • How does sickness behavior translate into pathology?

  8. The sickness inducing effects of peripheral IL-1 are mediated centrally (from Kent et al, 1992) IL-1b IL-1ra

  9. How can peripherally produced cytokines act in the brain? PAMPs Peripheral cytokines Brain targets HPA axis Fever Sickness activation behavior

  10. Humoral pathway Neural pathway Peripheral cytokines do not need to get into the brain because they are produced in the brain PAMPs Peripheral cytokines Brain cytokines PGE2 Brain targets HPA axis Fever Sickness activation behaviour

  11. IL-1b IL-1b ir NFkB ir AP 1-2 h BV NTS Visualization of IL-1 Receptors via NFkB Activation in the Rat Brain (Nadjar et al., 2003-2005) 2-4 h

  12. Vagotomy abrogates the induction of hypothalamic IL-1b expression and sickness behavior LPS/ IL-1 Social exploration Hypothalamic expression of IL-1b VGX Sham From Layé, Bluthe et al, 1995

  13. 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

  14. Why do we feel and behave in a sick way when we are ill? • How is organized the sickness response to cytokines? • How does sickness behavior translate into pathology?

  15. LPS LPS 24°C 6°C The behavioral effects of cytokines correspond to a reorganization of the host’s priorities (Aubert et al., 1997) Medical interpretation Behavioral alterations Internal state (weakness) Cytokines Motivational interpretation Environmental contingencies Internal state Behavioral alterations Cytokines 24°C

  16. MOTIVATIONAL INTERPRETATION OF FEAR Fear feelings Fear behavior Visceralarousal Fear Threat

  17. MOTIVATIONAL INTERPRETATION OF SICKNESS Fear feelings Fear behavior Visceralarousal Fear Threat Pathogenic micro- organisms Malaise Sickness behavior Visceral arousal Sickness

  18. 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…)

  19. Why do we feel and behave in a sick way when we are ill? • How is organized the sickness response to cytokines? • How does sickness behavior translate into pathology?

  20. Pathogen-associated molecular patterns Endogenous danger signals Peripheral proinflammatory cytokines Anti-inflammatory cytokines Cortisol AVP a-MSH Brain proinflammatory cytokines Non specific symptoms of disease Anorexia Anhedonia Cachexia Cognitive disorders Mood disorders Pain Fatigue

  21. 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.

  22. 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 • 5-10% • 18-39% • 15-40% • 15-40% • 15-60% • 20-30% See for review, Evans et al., Biological Psychiatry, 58, 2005

  23. Temporal Evolution of the Behavioral Symptoms Induced by Chronic Cytokine Therapy Mood and Cognitive Symptoms Depression Neurovegetative Symptoms (e.g., fatigue) Sickness Behavior Symptom Intensity Minimally responsive to antidepressants responsive to antidepressants W 1-4 W 4-8 W 8-12 Time on IFN-Alpha

  24. Initial MADRS Scores PredictDepressiveSymptoms Four Weeks Later 35 R=0.753 p<0.001 30 25 MADRS Score (D26) 20 IL-2 IL-2+IFN 15 Iv IFN 10 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

  25. Pituitary-adrenal response to IFNa predicts the occurrence of depressive symptoms ACTH Cortisol 800 * 35 # *** 700 *** 30 *** 600 * ** 25 * 500 *** 20 pg/ml 400 CORT (g/dl) 15 300 ** 10 200 ** 5 100 0 0 0h 1h 2h 3h 0h 1h 2h 3h IFN IFN Depressed patients (n=8) Capuron et al., Am J Psychiat, 2003. Non- depressed patients (n=8)

  26. R=-0.50 p<0.05 30 25 20 MADRS score 15 10 5 0 -60 -40 -20 0 20 40  TRP Depressed mood is specifically associated with decreased plasma tryptophan levels in IFNa-treated patients Tryptophan Non-depr MDD Symptom dimensions rTRP Depression -0.627* Anxiety -0.674** Cognitive -0.636** Neurovegetative -0.381 Somatic -0.220 ** p<0.01 Capuron et al., 2002, 2003

  27. 5-HTP IDO IFNg PAMPs Kynurenine 5-HT Decreased serotoninergic neurotransmission Quinolinic acid Alterated glutamatergic neurotransmission IDO = indoleamine 2,3 dioxygenase Immune stimuli activate a key enzyme in the metabolism of tryptophan Food Proteins Tryptophan

  28. BLOCKADE OF PROINFLAMMATORY CYTOKINE EXPRESSION BY MINOCYCLINE ABROGATES LPS-INDUCED DEPRESSIVE-LIKE BEHAVIOR Sal Sal ** 160 LPS LPS 120 FST Immobility (s) 80 40 Sal Mino Forced Swim Test 300 ** Tail Suspension Test 200 TST Immobility (s) 100 0 Sal Mino

  29. 160 120 FST Immobility (s) 80 40 Placebo 1-MT Saline Saline LPS LPS BLOCKADE OF IDO BY 1-METHYL-TRYPTOPHAN ABROGATES LPS-INDUCED DEPRESSIVE-LIKE BEHAVIOR * * 300 200 TST Immobility (s) 100 0 1-MT Placebo

  30. Aging is associated with chronic brain inflammation Adult age Anti-inflammatory cytokines Proinflammatory cytokines Aging Anti-inflammatory cytokines Proinflammatory cytokines (Johnson et al., 2003)

  31. Forced swim test A. b b 1 1 8 8 0 0 b b 24 h 1 1 6 6 0 0 b 1 8 0 Adult CON Adult CON Adult CON Adult CON Adult CON Adult CON Adult CON Adult CON Adult CON Adult CON Adult CON Adult CON Adult CON Adult CON Adult CON Adult CON Aged CON Aged CON Aged CON Aged CON Aged CON Aged CON Aged CON Aged CON Aged CON Aged CON Aged CON Aged CON b 1 1 4 4 0 0 1 6 0 Adult LPS Adult LPS Adult LPS Adult LPS Adult LPS Adult LPS Adult LPS Adult LPS Adult LPS Adult LPS Adult LPS Adult LPS Adult LPS Adult LPS Adult LPS Adult LPS Aged LPS Aged LPS Aged LPS Aged LPS Aged LPS Aged LPS Aged LPS Aged LPS Aged LPS Aged LPS Aged LPS Aged LPS 1 1 2 2 0 0 a a 1 4 0 Duration of Immobility (sec) Duration of Immobility (sec) 1 1 0 0 0 0 20 20 20 20 20 20 20 20 1 2 0 a Duration of Immobility (sec) a a 8 8 0 0 1 0 0 0 0 0 0 0 0 0 0 6 6 0 0 a 8 0 4 4 0 0 6 0 - - - - - - - - 20 20 20 20 20 20 20 20 2 2 0 0 4 0 0 0 2 0 A A d d u u l l t t A A d d u u l l t t A A g g e e d d A A g g e e d d - - - - - - - - 40 40 40 40 40 40 40 40 0 S S a a l l i i n n e e L L P P S S S S a a l l i i n n e e L L P P S S * * * * * * * * A d u l t A d u l t A g e d A g e d Social Behavior (% baseline) Social Behavior (% baseline) Social Behavior (% baseline) Social Behavior (% baseline) Social Behavior (% baseline) Social Behavior (% baseline) Social Behavior (% baseline) Social Behavior (% baseline) S a l i n e L P S S a l i n e L P S - - - - - - - - 60 60 60 60 60 60 60 60 . B. 1 1 4 4 0 0 * * * * * * * * b b 1 4 0 72 h 1 1 2 2 0 0 * * * * * * * * - - - - - - - - 80 80 80 80 80 80 80 80 b a a 1 2 0 ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ 1 1 0 0 0 0 *, *, *, *, *, *, *, *, *, *, *, *, *, *, *, - - - - - - - - 100 100 100 100 100 100 100 100 a 1 0 0 8 8 0 0 a a ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ a a Duration of Immobility (sec) Duration of Immobility (sec) * * * * * * * * *, *, *, *, *, *, *, *, * * * * * * * * 8 0 a a 6 6 0 0 Duration of Immobility (sec) ‡ ‡ ‡ ‡ ‡ ‡ 2 2 2 2 2 2 2 2 4 4 4 4 4 4 4 4 8 8 8 8 8 8 8 8 24 24 24 24 24 24 24 24 6 0 4 4 0 0 4 0 2 2 0 0 Hours Post Injection Hours Post Injection Hours Post Injection Hours Post Injection Hours Post Injection Hours Post Injection Hours Post Injection Hours Post Injection 2 0 0 0 0 A A d d u u l l t t A A d d u u l l t t A A g g e e d d A A g g e e d d S S a a l l i i n n e e L L P P S S S S a a l l i i n n e e L L P P S S A d u l t A d u l t A g e d A g e d S a l i n e L P S S a l i n e L P S and this chronic brain inflammation has functional consequences… Social exploration Adult CON Adult CON Adult CON Adult CON Adult CON Adult CON Adult CON Adult CON Aged CON Aged CON Aged CON Aged CON Aged CON Aged CON Adult LPS Adult LPS Adult LPS Adult LPS Adult LPS Adult LPS Adult LPS Adult LPS Aged LPS Aged LPS Aged LPS Aged LPS Aged LPS Aged LPS 20 20 20 20 0 0 0 0 - - - - 20 20 20 20 - - - - 40 40 40 40 * * * * Social Behavior (% baseline) Social Behavior (% baseline) Social Behavior (% baseline) Social Behavior (% baseline) - - - - 60 60 60 60 * * * * * * * * - - - - 80 80 80 80 *, *, *, *, *, *, - - - - 100 100 100 100 ‡ ‡ ‡ ‡ * * * * *, *, *, *, * * * * 2 2 2 2 4 4 4 4 8 8 8 8 24 24 24 24 Hours Post Injection (Godbout et al.)

  32. 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.

  33. These processes are amplified in situation of chronic inflammation including aging & obesity. Neuroimmune interactions represent new targets for health promoting compounds.

  34. Activation of brain cytokine signaling Chronic peripheral inflammation Risk factors for inflammatory disorders Risk factors for psychiatric disorders • Subjective health complaints: • Fatigue, Pain • Sleep disorders • Depressed mood • Cognitive alterations

  35. INVESTIGATIONS IN NEURO-IMMUNE PROGRAMMING Neonatal activation of the immune system (Variation factors: time, nature of the stimulus} Neural development Alterations in BW regulation adiposity, fever, HPA axis activity and reactivity Anxiety Neurodevelopmental hypothesis of autism and schizophrenia

More Related