From inflammation to sickness and depression: when the immune system subjugates the brain

Dantzer, R. & Kelley, K. W. Twenty years of research on cytokine-induced sickness behavior. Brain Behav. Immun. 21, 153–160 (2007).

Hart, B. L. Biological basis of the behavior of sick animals. Neurosci. Biobehav. Rev. 12, 123–137 (1988). The original description of sickness behaviour, its relationship with fever and adaptive value.

Dantzer, R. & Kelley, K. W. Stress and immunity: an integrated view of relationships between the brain and the immune system. Life Sci. 44, 1995–2008 (1989).

Dantzer, R. Cytokine-induced sickness behavior: where do we stand? Brain Behav. Immun. 15, 7–24 (2001).

Steptoe, A. (ed.) Depression and Physical Illness (Cambridge University Press, Cambridge, 2007).

Galea, I., Bechmann, I. & Perry, V. H. What is immune privilege (not)? Trends Immunol. 28, 12–18 (2007). A review of how the brain immune response differs from that in other organs.

Dantzer, R. in Psychoneuroimmunology (ed. Ader, R.) 271–280 (Elsevier, Amsterdam, 2007).

Bluthe, R. M. et al. Lipopolysaccharide induces sickness behaviour in rats by a vagal mediated mechanism. C. R. Acad. Sci. III 317, 499–503 (1994). The first demonstration that section of the vagus nerves blocks immune-to-brain communication and abrogates lipopolysacccharide-induced sickness behaviour without compromising the peripheral immune response.

Watkins, L. R. et al. Neurocircuitry of illness-induced hyperalgesia. Brain Res. 639, 283–299 (1994).

Romeo, H. E., Tio, D. L., Rahman, S. U., Chiappelli, F. & Taylor, A. N. The glossopharyngeal nerve as a novel pathway in immune-to-brain communication: relevance to neuroimmune surveillance of the oral cavity. J. Neuroimmunol. 115, 91–100 (2001).

Quan, N., Whiteside, M. & Herkenham, M. Time course and localization patterns of interleukin-1beta messenger RNA expression in brain and pituitary after peripheral administration of lipopolysaccharide. Neuroscience 83, 281–293 (1998).

Vitkovic, L. et al. Cytokine signals propagate through the brain. Mol. Psychiatry 5, 604–615 (2000).

Banks, W. A. The blood-brain barrier in psychoneuroimmunology. Neurol. Clin. 24, 413–419 (2006).

Konsman, J. P., Vigues, S., Mackerlova, L., Bristow, A. & Blomqvist, A. Rat brain vascular distribution of interleukin-1 type-1 receptor immunoreactivity: relationship to patterns of inducible cyclooxygenase expression by peripheral inflammatory stimuli. J. Comp. Neurol. 472, 113–129 (2004).

Schiltz, J. C. & Sawchenko, P. E. Distinct brain vascular cell types manifest inducible cyclooxygenase expression as a function of the strength and nature of immune insults. J. Neurosci. 22, 5606–5618 (2002).

Dantzer, R., Konsman, J. P., Bluthe, R. M. & Kelley, K. W. Neural and humoral pathways of communication from the immune system to the brain: parallel or convergent? Auton. Neurosci. 85, 60–65 (2000).

Reyes, T. M. & Sawchenko, P. E. Involvement of the arcuate nucleus of the hypothalamus in interleukin-1-induced anorexia. J. Neurosci. 22, 5091–5099 (2002).

Ericsson, A., Kovacs, K. J. & Sawchenko, P. E. A functional anatomical analysis of central pathways subserving the effects of interleukin-1 on stress-related neuroendocrine neurons. J. Neurosci. 14, 897–913 (1994).

Dinarello, C. A. Interleukin-1. Cytokine Growth Factor Rev. 8, 253–265 (1997).

Parnet, P., Kelley, K. W., Bluthe, R. M. & Dantzer, R. Expression and regulation of interleukin-1 receptors in the brain. Role in cytokines-induced sickness behavior. J. Neuroimmunol. 125, 5–14 (2002).

van Dam, A. M., Brouns, M., Louisse, S. & Berkenbosch, F. Appearance of interleukin-1 in macrophages and in ramified microglia in the brain of endotoxin-treated rats: a pathway for the induction of non-specific symptoms of sickness? Brain Res. 588, 291–296 (1992). The first demonstration that peripherally administered lipopolysaccharide induces the expression of IL-1β in the brain.

Laye, S., Parnet, P., Goujon, E. & Dantzer, R. Peripheral administration of lipopolysaccharide induces the expression of cytokine transcripts in the brain and pituitary of mice. Brain Res. Mol. Brain Res. 27, 157–162 (1994).

Quan, N., Stern, E. L., Whiteside, M. B. & Herkenham, M. Induction of pro-inflammatory cytokine mRNAs in the brain after peripheral injection of subseptic doses of lipopolysaccharide in the rat. J. Neuroimmunol. 93, 72–80 (1999).

Gatti, S. & Bartfai, T. Induction of tumor necrosis factor-alpha mRNA in the brain after peripheral endotoxin treatment: comparison with interleukin-1 family and interleukin-6. Brain Res. 624, 291–294 (1993).

Breder, C. D. et al. Regional induction of tumor necrosis factor alpha expression in the mouse brain after systemic lipopolysaccharide administration. Proc. Natl Acad. Sci. USA 91, 11393–11397 (1994).

Carmichael, M. D. et al. Role of brain IL-1beta on fatigue after exercise-induced muscle damage. Am. J. Physiol. Regul. Integr. Comp. Physiol. 291, R1344–1348 (2006).

Ohdo, S., Koyanagi, S., Suyama, H., Higuchi, S. & Aramaki, H. Changing the dosing schedule minimizes the disruptive effects of interferon on clock function. Nature Med. 7, 356–360 (2001).

Cavadini, G. et al. TNF-{alpha} suppresses the expression of clock genes by interfering with E-box-mediated transcription. Proc. Natl Acad. Sci. USA (2007).

Sparkman, N. L. et al. Interleukin-6 facilitates lipopolysaccharide-induced disruption in working memory and expression of other proinflammatory cytokines in hippocampal neuronal cell layers. J. Neurosci. 26, 10709–10716 (2006).

Heyen, J. R., Ye, S., Finck, B. N. & Johnson, R. W. Interleukin (IL)-10 inhibits IL-6 production in microglia by preventing activation of NF-kappaB. Brain Res. Mol. Brain Res. 77, 138–147 (2000).

Strle, K. et al. Novel activity of an anti-inflammatory cytokine: IL-10 prevents TNFalpha-induced resistance to IGFI in myoblasts. J. Neuroimmunol. (in the press).

Bluthe, R. M. et al. Central injection of IL-10 antagonizes the behavioural effects of lipopolysaccharide in rats. Psychoneuroendocrinology 24, 301–311 (1999).

Dantzer, R., Gheusi, G., Johnson, R. W. & Kelley, K. W. Central administration of insulin-like growth factor-1 inhibits lipopolysaccharide-induced sickness behavior in mice. Neuroreport 10, 289–292 (1999).

Bluthe, R. M., Kelley, K. W. & Dantzer, R. Effects of insulin-like growth factor-I on cytokine-induced sickness behavior in mice. Brain Behav. Immun. 20, 57–63 (2006).

Leon, L. R., Kozak, W., Rudolph, K. & Kluger, M. J. An antipyretic role for interleukin-10 in LPS fever in mice. Am. J. Physiol. 276, R81–89 (1999).

Ye, S. M. & Johnson, R. W. Increased interleukin-6 expression by microglia from brain of aged mice. J. Neuroimmunol. 93, 139–148 (1999).

Ye, S. M. & Johnson, R. W. An age-related decline in interleukin-10 may contribute to the increased expression of interleukin-6 in brain of aged mice. Neuroimmunomodulation 9, 183–192 (2001).

Huang, Y., Henry, C. J., Dantzer, R., Johnson, R. W. & Godbout, J. P. Exaggerated sickness behavior and brain proinflammatory cytokine expression in aged mice in response to intracerebroventricular lipopolysaccharide. Neurobiol. Aging (2007).

O'Connor, J. C. et al. IL-1beta-mediated innate immunity is amplified in the db/db mouse model of type 2 diabetes. J. Immunol. 174, 4991–4997 (2005).

Yirmiya, R. et al. Cytokines, “depression due to a general medical condition” and antidepressant drugs. Adv. Exp. Med. Biol. 461, 283–316 (1999).

Raison, C. L., Capuron, L. & Miller, A. H. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 27, 24–31 (2006). An excellent review of the clinical features of cytokine-induced depression and its possible mechanisms.

Nemeroff, C. B. & Vale, W. W. The neurobiology of depression: inroads to treatment and new drug discovery. J. Clin. Psychiatry 66, Suppl 7, 5–13 (2005).

Smith, R. S. The macrophage theory of depression. Med. Hypotheses 35, 298–306 (1991).

Maes, M., Smith, R. & Scharpe, S. The monocyte-T-lymphocyte hypothesis of major depression. Psychoneuroendocrinology 20, 111–116 (1995).

Irwin, M. R. & Miller, A. H. Depressive disorders and immunity: 20 years of progress and discovery. Brain Behav. Immun. 21, 374–383 (2007).

Denicoff, K. D. et al. The neuropsychiatric effects of treatment with interleukin-2 and lymphokine-activated killer cells. Ann. Intern. Med. 107, 293–300 (1987).

Renault, P. F. et al. Psychiatric complications of long-term interferon alfa therapy. Arch. Intern. Med. 147, 1577–1580 (1987).

Capuron, L. et al. Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology 26, 643–652 (2002).

Capuron, L., Ravaud, A. & Dantzer, R. Early depressive symptoms in cancer patients receiving interleukin 2 and/or interferon alfa-2b therapy. J. Clin. Oncol. 18, 2143–2151 (2000).

Constant, A. et al. Mood alterations during interferon-alfa therapy in patients with chronic hepatitis C: evidence for an overlap between manic/hypomanic and depressive symptoms. J. Clin. Psychiatry 66, 1050–1057 (2005).

Capuron, L. & Ravaud, A. Prediction of the depressive effects of interferon alfa therapy by the patient's initial affective state. N. Engl. J. Med. 340, 1370 (1999).

Capuron, L. et al. Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy. Am. J. Psychiatry 160, 1342–1345 (2003).

Frenois, F. et al. Lipopolysaccharide induces delayed FosB/DeltaFosB immunostaining within the mouse extended amygdala, hippocampus and hypothalamus, that parallel the expression of depressive-like behavior. Psychoneuroendocrinology 32, 516–531 (2007).

Simmons, D. A. & Broderick, P. A. Cytokines, stressors, and clinical depression: augmented adaptation responses underlie depression pathogenesis. Prog. Neuropsychopharmacol. Biol. Psychiatry 29, 793–807 (2005).

Merali, Z., Brennan, K., Brau, P. & Anisman, H. Dissociating anorexia and anhedonia elicited by interleukin-1beta: antidepressant and gender effects on responding for “free chow” and “earned” sucrose intake. Psychopharmacology (Berl.) 165, 413–418 (2003).

Capuron, L. et al. Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol. Psychiatry 7, 468–473 (2002). A landmark paper demonstrating that repeated activation of the immune system by systemic administration of IL-2 and IFN-α to cancer patients induces a drastic fall in plasma tryptophan levels that is positively correlated to the depression scores.

Ruhe, H. G., Mason, N. S. & Schene, A. H. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. Mol. Psychiatry 12, 331–359 (2007).

Wirleitner, B., Neurauter, G., Schrocksnadel, K., Frick, B. & Fuchs, D. Interferon-gamma-induced conversion of tryptophan: immunologic and neuropsychiatric aspects. Curr. Med. Chem. 10, 1581–1591 (2003).

Lestage, J., Verrier, D., Palin, K. & Dantzer, R. The enzyme indoleamine 2, 3-dioxygenase is induced in the mouse brain in response to peripheral administration of lipopolysaccharide and superantigen. Brain Behav. Immun. 16, 596–601 (2002).

Moreau, M. et al. Bacille Calmette-Guerin inoculation induces chronic activation of peripheral and brain indoleamine 2, 3-dioxygenase in mice. J. Infect. Dis. 192, 537–544 (2005).

Muller, N. & Schwarz, M. J. The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression. Mol. Psychiatry 12, 988–1000 (2007).

Dunn, A. J., Swiergiel, A. H. & de Beaurepaire, R. Cytokines as mediators of depression: what can we learn from animal studies? Neurosci. Biobehav. Rev. 29, 891–909 (2005).

Zhu, C. B., Blakely, R. D. & Hewlett, W. A. The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Neuropsychopharmacology 31, 2121–2131 (2006).

Cai, W. et al. Interferon-alpha-induced modulation of glucocorticoid and serotonin receptors as a mechanism of depression. J. Hepatol. 42, 880–887 (2005).

Pariante, C. M. Depression, stress and the adrenal axis. J. Neuroendocrinol. 15, 811–812 (2003).

Berkenbosch, F., van Oers, J., del Rey, A., Tilders, F. & Besedovsky, H. Corticotropin-releasing factor-producing neurons in the rat activated by interleukin-1. Science 238, 524–526 (1987).

Grinevich, V. et al. Hypothalamic pituitary adrenal axis and immune responses to endotoxin in rats with chronic adjuvant-induced arthritis. Exp. Neurol. 178, 112–123 (2002).

Swaab, D. F., Bao, A. M. & Lucassen, P. J. The stress system in the human brain in depression and neurodegeneration. Ageing Res. Rev. 4, 141–194 (2005).

Holsboer, F. Corticotropin-releasing hormone modulators and depression. Curr. Opin. Investig. Drugs 4, 46–50 (2003).

Pace, T. W., Hu, F. & Miller, A. H. Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression. Brain Behav. Immun. 21, 9–19 (2007).

Raison, C. L. & Miller, A. H. When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am. J. Psychiatry 160, 1554–1565 (2003).

Fitzgerald, P. B., Laird, A. R., Maller, J. & Daskalakis, Z. J. A meta-analytic study of changes in brain activation in depression. Hum. Brain Mapp. (2007).

Capuron, L. et al. Basal ganglia hypermetabolism and symptoms of fatigue during interferon-alpha therapy. Neuropsychopharmacology (2007).

Capuron, L. et al. Anterior cingulate activation and error processing during interferon-alpha treatment. Biol. Psychiatry 58, 190–196 (2005).

Stone, E. A., Lehmann, M. L., Lin, Y. & Quartermain, D. Depressive behavior in mice due to immune stimulation is accompanied by reduced neural activity in brain regions involved in positively motivated behavior. Biol. Psychiatry 60, 803–811 (2006).

Phillips, M. L., Drevets, W. C., Rauch, S. L. & Lane, R. Neurobiology of emotion perception II: Implications for major psychiatric disorders. Biol. Psychiatry 54, 515–528 (2003).

Lowry, C. A. et al. Identification of an immune-responsive mesolimbocortical serotonergic system: potential role in regulation of emotional behavior. Neuroscience 146, 756–772 (2007).

Craig, A. D. How do you feel? Interoception: the sense of the physiological condition of the body. Nature Rev. Neurosci. 3, 655–666 (2002).

Frasure-Smith, N. & Lesperance, F. Depression and coronary artery disease. Herz 31, Suppl 3, 64–68 (2006).

Tyring, S. et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet 367, 29–35 (2006).

Muller, N. et al. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol. Psychiatry 11, 680–684 (2006).

van den Biggelaar, A. H. et al. Inflammation and interleukin-1 signaling network contribute to depressive symptoms but not cognitive decline in old age. Exp. Gerontol. 42, 693–701 (2007).

Godbout, J. P. et al. Aging exacerbates depressive-like behavior in mice in response to activation of the peripheral innate immune system. Neuropsychopharmacology (in the press).

Airan, R. D. et al. High-speed imaging reveals neurophysiological links to behavior in an animal model of depression. Science 317, 819–823 (2007).

Sheng, H. et al. Transforming growth factor-beta1 enhances Ha-ras-induced expression of cyclooxygenase-2 in intestinal epithelial cells via stabilization of mRNA. J. Biol. Chem. 275, 6628–6635 (2000).

Babcock, T. A. & Carlin, J. M. Transcriptional activation of indoleamine dioxygenase by interleukin 1 and tumor necrosis factor alpha in interferon-treated epithelial cells. Cytokine 12, 588–594 (2000).

Siegert, R. J. & Abernethy, D. A. Depression in multiple sclerosis: a review. J. Neurol. Neurosurg. Psychiatry 76, 469–475 (2005).

Pollak, Y., Ovadia, H., Orion, E., Weidenfeld, J. & Yirmiya, R. The EAE-associated behavioral syndrome: I. Temporal correlation with inflammatory mediators. J. Neuroimmunol. 137, 94–99 (2003).

Pollak, Y., Ovadia, H., Orion, E. & Yirmiya, R. The EAE-associated behavioral syndrome: II. Modulation by anti-inflammatory treatments. J. Neuroimmunol. 137, 100–108 (2003).

McMahon, E. J., Bailey, S. L., Castenada, C. V., Waldner, H. & Miller, S. D. Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis. Nature Med. 11, 335–339 (2005).

Miller, S. D., McMahon, E. J., Schreiner, B. & Bailey, S. L. Antigen presentation in the CNS by myeloid dendritic cells drives progression of relapsing experimental autoimmune encephalomyelitis. Ann. NY Acad. Sci. 1103, 179–191 (2007).

Johnson, D. R., O'Connor, J. C., Hartman, M. E., Tapping, R. I. & Freund, G. G. Acute hypoxia activates the neuroimmune system, which diabetes exacerbates. J. Neurosci. 27, 1161–1166 (2007).

Ohayon, M. M. The effects of breathing-related sleep disorders on mood disturbances in the general population. J. Clin. Psychiatry 64, 1195–1200; quiz, 1274–1276 (2003).

Borson, S., Claypoole, K. & McDonald, G. J. Depression and chronic obstructive pulmonary disease: treatment trials. Semin. Clin. Neuropsychiatry 3, 115–130 (1998).

Schwarcz, R. The kynurenine pathway of tryptophan degradation as a drug target. Curr. Opin. Pharmacol. 4, 12–17 (2004).

Combrinck, M. I., Perry, V. H. & Cunningham, C. Peripheral infection evokes exaggerated sickness behaviour in pre-clinical murine prion disease. Neuroscience 112, 7–11 (2002).

Cunningham, C., Wilcockson, D. C., Campion, S., Lunnon, K. & Perry, V. H. Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J. Neurosci. 25, 9275–9284 (2005).

Godbout, J. P. et al. Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. Faseb J. 19, 1329–1331 (2005).

Schroder, K., Sweet, M. J. & Hume, D. A. Signal integration between IFNgamma and TLR signalling pathways in macrophages. Immunobiology 211, 511–524 (2006).

Perry, V. H., Cunningham, C. & Holmes, C. Systemic infections and inflammation affect chronic neurodegeneration. Nature Rev. Immunol. 7, 161–167 (2007). A presentation of the concept of priming of the microglial compartment during chronic brain inflammation and its role in the exaggerated response to systemic infections.

Stichel, C. C. & Luebbert, H. Inflammatory processes in the aging mouse brain: participation of dendritic cells and T-cells. Neurobiol. Aging (2006).

Silverman, A. J., Sutherland, A. K., Wilhelm, M. & Silver, R. Mast cells migrate from blood to brain. J. Neurosci. 20, 401–408 (2000).

of peripheral lipopolysaccharide administration on contextual and auditory-cue fear conditioning. Brain Behav. Immun. 12, 212–229 (1998).

Vereker, E., O'Donnell, E. & Lynch, M. A. The inhibitory effect of interleukin-1beta on long-term potentiation is coupled with increased activity of stress-activated protein kinases. J. Neurosci. 20, 6811–6819 (2000).

Sweller, J. Cognitive load during problem solving: effects on learning. Cognitive Sci. 12, 257–285 (1988).

Blum, D., Chtarto, A., Tenenbaum, L., Brotchi, J. & Levivier, M. Clinical potential of minocycline for neurodegenerative disorders. Neurobiol. Dis. 17, 359–366 (2004).