Inflammation as a Key Player in Fatigue: Evidence and Consequences Robert Dantzer

1. Inflammation as a Key Player in Fatigue: Evidence and Consequences Robert Dantzer Integrative Immunology & Behavior Program University of Illinois at Urbana-Champaign (dantzer@uiuc.edu)

2. Fatigue in breast cancer survivors • Occurrence of severe fatigue in one third of breast cancer survivors associated with depression, pain, and sleep disturbances (Bower et al., 2000) • Fatigue associated with biomarkers of inflammation and flattened diurnal cortisol slope (Bower et al., 2002, 2005, 2006) • Single nucleotide polymorphism in IL-1b gene is a potential risk factor for the occurrence of fatigue in breast cancer survivors (Bower et al., 2008) => What is the relationship between inflammation and fatigue?

3. Peripheral inflammation activates brain cytokine signaling which results in sickness behavior Intense and/or prolonged activation of the innate immune system induces depression in vulnerable individuals. Depression includes both neurovegetative symptoms and psychological symptoms. Fatigue is an important neurovegetative component of inflammation-associated depression. Because aging is associated with inflammation, aged subjects have a higher risk of developing symptoms of depression and fatigue.

4. Sickness Fatigue Nod Inflammasome Caspase-1 Pathogen-associated molecular patterns Oxidative stress (From Raison et al. Trends Immunol, 2006)

5. Intraperitoneal lipopolysaccharide or IL-1b induces the expression of IL-1b in the brain and sickness behavior in a vagal dependent manner Social exploration Hypothalamic expression of IL-1b VGX LPS/IL-1 Sham From Layé, Bluthe et al, 1995

6. Peripheral inflammation activates brain cytokine signaling which results in sickness behavior Intense and/or prolonged activation of the innate immune system induces depression in vulnerable individuals. Depression includes both neurovegetative symptoms and psychological symptoms. Fatigue is an important neurovegetative component of inflammation-associated depression. Because aging is associated with inflammation, aged subjects have a higher risk of developing symptoms of depression and fatigue.

7. Inflammation-associated depression • PRECLINICAL EVIDENCE: • Acute and chronic activation of the immune system in laboratory rodents induces sickness behavior followed by signs of depression (Yirmiya, 1996; Frenois et al., 2007; O’Connor et al., 2008) • CLINICAL EVIDENCE: • - Depressed patients can show a clinical biology profile of inflammation (Maes, 1995) • - Administration of IFNa and/or IL-2 to cancer patients induces sickness in all patients followed by symptoms of depression (Capuron et al., 2000)

8. Symptom dimensions in inflammation-associated depression BDI Factor Analysis Depressive symptoms Neurovegetative Fatigue Loss of energy Sleep alterations Changes in appetite Anhedonia/loss of interest Indecisiveness Concentration difficulties Mood Sadness Pessimism Suicidal thoughts Crying Agitation Irritability Affective-cognitive Failure Guilty feelings Punishment feelings Self-dislike Self-criticism Worthlessness

9. Pretreatment with the SSRI paroxetine improves the psychological but not the neurovegetative dimension of interferon-alpha induced depression (n=20/group) (Musselman et al., NEJM, 2001 Capuron et al, Neuropsychopharmacogy, 2002)

10. (Part of Vietman Era Study Registry, Twins’ Heart Study) Symptom dimensions associated with the metabolic syndrome Total depression Neurovegetative * ** 7 4 6 5 3 Total score Beck 4 Neurovegetative subscore 2 3 2 1 1 0 0 Met. Synd. (n=145) Non Met. Synd (n=176) ** p<0.01 Affective-cognitive Mood 4 4 3 3 Affective-cognitive Mood subscore subscore 2 2 1 1 0 0

11. Inflammatory markers Hs CRP IL6 TNF-a *** *** 3 4 3 3 2 2 pg/mL pg/mL mg/L 2 1 1 1 0 0 0 sTNFR-II sIL6R 3 30 * Met. Synd. (n=145) 25 Non Met. Synd (n=176) 2 20 pg/mL pg/mL 15 *** p<0.001 *p<0.05 1 10 5 0 0

12. Chronic administration of IFNa induces fatigue that is associated with basal ganglia hypermetabolism Changes in regional brain glucose metabolism • 12 patients with malignant melanoma studied before and after (4 weeks) the initiation of IFNa therapy • Energy subscale of the Visual Analog Scale of fatigue: • Scored items: • energetic • active • vigorous • efficient • lively • Mean score: 34.0 -> 21.4 (Capuron et al, Neuropsychopharmacology, 2007)

13. Peripheral inflammation activates brain cytokine signaling which results in sickness behavior Intense and/or prolonged activation of the innate immune system induces depression in vulnerable individuals. Depression includes both neurovegetative symptoms and psychological symptoms. Fatigue is an important neurovegetative component of inflammation-associated depression. Because aging is associated with inflammation, aged subjects have a higher risk of developing symptoms of depression and fatigue.

14. Aging is associated with enhanced brain cytokine expression Adult individual Anti-inflammatory cytokines Proinflammatory cytokines Aged individual Anti-inflammatory cytokines Proinflammatory cytokines Whole brain 4 h post LPS vs. sal (Godbout et al., 2005) (Johnson et al., 2003)

15. * * * * .5 75 80 .4 60 60 .3 45 IL-10 (ng/ml) 40 .2 30 20 .1 15 0 0 0 + + 3 m 24 m Production of IL-6 and IL-10 by glia from adult and aged mice LPS, 20 ng/ml A B 24 18 IL-10 (ng/ml) IL-6 (ng/ml) 12 IL-6 (ng/ml) 6 0 + + LPS LPS 3 m 24 m 3 m 24 m 3 m 24 m Age Age Ye and Johnson, 2001; Neuroimmunomodulation 9:183-192

16. 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 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 20 20 20 20 20 20 20 20 0 0 0 0 0 0 0 0 - - - - - - - - 20 20 20 20 20 20 20 20 - - - - - - - - 40 40 40 40 40 40 40 40 * * * * * * * * Social Behavior (% baseline) Social Behavior (% baseline) Social Behavior (% baseline) Social Behavior (% baseline) Social Behavior (% baseline) Social Behavior (% baseline) Social Behavior (% baseline) Social Behavior (% baseline) - - - - - - - - 60 60 60 60 60 60 60 60 * * * * * * * * * * * * * * * * - - - - - - - - 80 80 80 80 80 80 80 80 ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ *, *, *, *, *, *, *, *, *, *, *, *, *, *, *, - - - - - - - - 100 100 100 100 100 100 100 100 ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ * * * * * * * * *, *, *, *, *, *, *, *, * * * * * * * * 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 Hours Post Injection Hours Post Injection Hours Post Injection Hours Post Injection Hours Post Injection Hours Post Injection Hours Post Injection Hours Post Injection and this chronic brain inflammation has functional consequences in terms of sickness… 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 ‡ ‡ ‡ ‡ * * * * *, *, *, *, * * * * (Godbout et al, Faaseb J, 2005) 2 2 2 2 4 4 4 4 8 8 8 8 24 24 24 24 Hours Post Injection

17. 1 1 4 4 0 0 b b 1 1 2 2 0 0 a a * 1 1 0 0 0 0 8 8 0 0 a a 400 a a Duration of Immobility (sec) Duration of Immobility (sec) 6 6 0 0 300 4 4 0 0 Duration of Immobility (sec) 2 2 0 0 200 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 100 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 0 Adult Saline Adult LPS Aged Saline Aged LPS and depressive-like behavior! 72 h post-LPS Forced Swim Test Tail Suspension Test (Godbout et al, 2008, Neuropsychopharmacology)

18. Motor Coordination (Rotarod) Exhaustive Fatigue (Treadmill) IL-1β mRNA in Cerebellum 85% 60% 57% 43% Fold change Time to Fatigue (min) Performance (Seconds) WT IL-10 KO WT IL-10 KO WT IL-10 KO Saline LPS Fatigue and Deficits in Motor Coordination Induced by LPS are Exacerbated in IL-10 Knockout Mice (Krzyston et al., Am J Physiol Regul Integr Comp Physiol, 2008)

19. Where are we now? Chronic Activation of Brain Cytokine Signaling Chronic Peripheral Inflammation Risk Factors for Psychiatric/Behavioral Disorders Risk Factors for Inflammatory Disorders • Subjective Health Complaints: • Fatigue • Sleep Disorders • Depressed Mood • Cognitive Alterations

20. Where do we go from there? At the clinical level: Is fatigue associated with inflammation in aged subjects and is it part of a larger syndrome including other non-specific symptoms of inflammation (including neurovegetative and psychological symptoms)? => epidemiological studies At the preclinical level: What are the intermediate mechanisms between inflammation and fatigue (proinflammatory vs. anti-inflammatory cytokines balance, IDO, IGF-1, DA, etc)? => mechanistic studies

21. Percent of control 1MT-SAL . SAL-SAL 125 100 75 1MT-LPS 50 . SAL-LPS 25 * 0 * 0 , 0 . 0 0 0 1 2 3 4 5 Day(s) post-LPS Blockade of IDO by 1-MT attenuates the delayed effect of LPS on voluntary wheel-running a B l e s i e n