Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

Key Points

  • Infections cause people to become sick and change their behaviour. They develop fever, sleep poorly, eat less, experience difficulty with memory and learning, withdraw socially and complain of pain and fatigue.

  • Glial and macrophage-like cells in the brain respond to peripheral infection by synthesizing the same pro-inflammatory and anti-inflammatory cytokines as those produced by leukocytes. Several immune-to-brain communication pathways act in parallel; these include a fast neural afferent pathway and a slower humoral pathway that requires a relay in circumventricular organs and the brain vasculature.

  • The predominant pro-inflammatory cytokines that cause behavioural signs of sickness are interleukin-1β and tumour necrosis factor-α (TNF-α).

  • Inflammation and sickness place a burden on working memory by reducing the ability of the short-term memory register to process environmental stimuli. This effect is likely to be responsible for the alterations in cognition that are caused by inflammation.

  • Sickness is as normal to infection as the fear response is to a threatening predator. Its purpose is to promote survival of the organism.

  • If infections do not resolve and peripheral inflammation continues unabated, clinical depression can develop over a background of sickness behaviour.

  • A mechanism for inflammation-associated depression is shunting of tryptophan away from serotonin synthesis, by activation of indoleamine 2,3 dioxygenase (IDO), an enzyme that is predominantly synthesized by myeloid cells, such as macrophages and microglia.

  • IDO activity is stimulated mainly by TNF-α and interferon-γ. This leads to the production of neuroactive tryptophan metabolites that can induce depression-like behaviour by altering glutamatergic neurotransmission.

  • Ageing, obesity and other conditions associated with chronic inflammation increase the risk of development and persistence of inflammation-associated sickness and depression.


In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour. When activation of the peripheral immune system continues unabated, such as during systemic infections, cancer or autoimmune diseases, the ensuing immune signalling to the brain can lead to an exacerbation of sickness and the development of symptoms of depression in vulnerable individuals. These phenomena might account for the increased prevalence of clinical depression in physically ill people. Inflammation is therefore an important biological event that might increase the risk of major depressive episodes, much like the more traditional psychosocial factors.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Pathways that transduce immune signals from the periphery to the brain.
Figure 2: Increased brain cytokine signalling impairs learning and memory.
Figure 3: LPs-increased depression-like behaviour in mice.
Figure 4: Depression as a consequence of decompensation of the mechanisms that regulate sickness.


  1. 1

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

    CAS  PubMed  Google Scholar 

  2. 2

    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.

    CAS  Google Scholar 

  3. 3

    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).

    CAS  PubMed  Google Scholar 

  4. 4

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

    CAS  PubMed  Google Scholar 

  5. 5

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

    Google Scholar 

  6. 6

    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.

    CAS  Google Scholar 

  7. 7

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

    Google Scholar 

  8. 8

    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.

    CAS  Google Scholar 

  9. 9

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

    CAS  PubMed  Google Scholar 

  10. 10

    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).

    CAS  PubMed  Google Scholar 

  11. 11

    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).

    CAS  Google Scholar 

  12. 12

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

    CAS  Google Scholar 

  13. 13

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

    PubMed  Google Scholar 

  14. 14

    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).

    Google Scholar 

  15. 15

    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).

    CAS  PubMed  Google Scholar 

  16. 16

    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).

    CAS  PubMed  Google Scholar 

  17. 17

    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).

    CAS  PubMed  Google Scholar 

  18. 18

    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).

    CAS  PubMed  Google Scholar 

  19. 19

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

    CAS  PubMed  Google Scholar 

  20. 20

    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).

    CAS  PubMed  Google Scholar 

  21. 21

    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.

    CAS  PubMed  Google Scholar 

  22. 22

    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).

    CAS  PubMed  Google Scholar 

  23. 23

    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).

    CAS  PubMed  Google Scholar 

  24. 24

    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).

    CAS  PubMed  Google Scholar 

  25. 25

    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).

    CAS  PubMed  Google Scholar 

  26. 26

    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).

    CAS  PubMed  Google Scholar 

  27. 27

    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).

    CAS  PubMed  Google Scholar 

  28. 28

    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).

  29. 29

    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).

    CAS  PubMed  Google Scholar 

  30. 30

    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).

    CAS  PubMed  Google Scholar 

  31. 31

    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).

  32. 32

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

    CAS  PubMed  Google Scholar 

  33. 33

    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).

    CAS  PubMed  Google Scholar 

  34. 34

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    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).

    CAS  PubMed  Google Scholar 

  36. 36

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

    CAS  PubMed  Google Scholar 

  37. 37

    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).

    CAS  PubMed  Google Scholar 

  38. 38

    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).

  39. 39

    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).

    CAS  PubMed  Google Scholar 

  40. 40

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

    CAS  PubMed  Google Scholar 

  41. 41

    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.

    CAS  PubMed  Google Scholar 

  42. 42

    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).

    CAS  PubMed  Google Scholar 

  43. 43

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

    CAS  PubMed  Google Scholar 

  44. 44

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

    CAS  PubMed  Google Scholar 

  45. 45

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

    CAS  PubMed  Google Scholar 

  46. 46

    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).

    CAS  PubMed  Google Scholar 

  47. 47

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

    CAS  PubMed  Google Scholar 

  48. 48

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

    CAS  Google Scholar 

  49. 49

    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).

    CAS  Google Scholar 

  50. 50

    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).

    CAS  PubMed  Google Scholar 

  51. 51

    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).

    CAS  PubMed  Google Scholar 

  52. 52

    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).

    PubMed  Google Scholar 

  53. 53

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    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).

    CAS  PubMed  Google Scholar 

  55. 55

    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).

    CAS  Google Scholar 

  56. 56

    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.

    CAS  PubMed  Google Scholar 

  57. 57

    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).

    CAS  PubMed  Google Scholar 

  58. 58

    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).

    CAS  PubMed  Google Scholar 

  59. 59

    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).

    CAS  PubMed  Google Scholar 

  60. 60

    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).

    CAS  PubMed  Google Scholar 

  61. 61

    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).

    CAS  PubMed  Google Scholar 

  62. 62

    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).

    CAS  PubMed  Google Scholar 

  63. 63

    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).

    CAS  PubMed  Google Scholar 

  64. 64

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

    CAS  PubMed  Google Scholar 

  65. 65

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

    PubMed  Google Scholar 

  66. 66

    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).

    CAS  Google Scholar 

  67. 67

    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).

    CAS  PubMed  Google Scholar 

  68. 68

    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).

    CAS  PubMed  Google Scholar 

  69. 69

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

    CAS  PubMed  Google Scholar 

  70. 70

    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).

    CAS  Google Scholar 

  71. 71

    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).

    Google Scholar 

  72. 72

    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).

  73. 73

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

  74. 74

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

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    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).

    CAS  PubMed  Google Scholar 

  76. 76

    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).

    PubMed  Google Scholar 

  77. 77

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

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

    CAS  Google Scholar 

  79. 79

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

    PubMed  Google Scholar 

  80. 80

    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).

    CAS  Google Scholar 

  81. 81

    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).

    CAS  PubMed  Google Scholar 

  82. 82

    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).

    CAS  PubMed  Google Scholar 

  83. 83

    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).

  84. 84

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

    CAS  PubMed  Google Scholar 

  85. 85

    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).

    CAS  PubMed  Google Scholar 

  86. 86

    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).

    CAS  PubMed  Google Scholar 

  87. 87

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

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    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).

    CAS  PubMed  Google Scholar 

  89. 89

    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).

    CAS  PubMed  Google Scholar 

  90. 90

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    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).

    CAS  Google Scholar 

  92. 92

    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).

    CAS  PubMed  Google Scholar 

  93. 93

    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).

    PubMed  Google Scholar 

  94. 94

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

    CAS  PubMed  Google Scholar 

  95. 95

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

    CAS  PubMed  Google Scholar 

  96. 96

    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).

    CAS  PubMed  Google Scholar 

  97. 97

    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).

    CAS  PubMed  Google Scholar 

  98. 98

    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).

    CAS  PubMed  Google Scholar 

  99. 99

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

    CAS  PubMed  Google Scholar 

  100. 100

    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.

    CAS  Google Scholar 

  101. 101

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

  102. 102

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

    CAS  PubMed  Google Scholar 

  103. 103

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

  104. 104

    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).

    CAS  PubMed  Google Scholar 

  105. 105

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

    Google Scholar 

  106. 106

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

    CAS  PubMed  Google Scholar 

Download references


The authors' work described here is supported by grants from the National Institute of Mental Health (NIMH), the National Institute on Aging (NIA) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). R.D. (R01 MH 079829 and R01 MH 71349), K.W.K. (R01 MH 51569 and R01 AG 029573) R.W.J. (R01 AG 023580, AG 0616710, MH 069148 and R21 DA 024443) and G.G.F (R01 DK 064862). The authors thank R. -M. Bluthe, N. Castanon, S. Laye, P. Parnet, J. P. Konsman, J. Lestage, L. Capuron, C. Dantzer and their Ph.D. students for their valuable contribution to many of the results and concepts presented in this Review.

Author information



Corresponding author

Correspondence to Robert Dantzer.

Related links

Related links


Robert Dantzer's homepage


Accessory immune cells

Cells such as macrophages and dendritic cells that are required for, but do not actually mediate, adaptive immune responses of T and B lymphocytes.

Motivational state

A central state that re-organizes perception and action.


A response of tissues to injury or irritation that is characterized by pain, swelling, redness and heat.

Physical illness

An infectious, autoimmune or oncogenic disease in which physical rather than psychological symptoms of the diseased tissue or organ predominate.

Choroid plexus

A capillary bed that is covered by transporting ependymal cells and that protrudes into the cerebral ventricles. The ependymal cells are responsible for producing cerebral spinal fluid.


The three protective layers of tissue that surround the brain and spinal cord.


Cellular communication molecule synthesized from arachidonic acid. Specific compounds are designated by adding a letter to indicate the type of substituents found on the hydrocarbon skeleton and a subscript to indicate the number of double bonds in the hydrocarbon skeleton.

Vagal nerve

The 10th pair of cranial nerves that innervates the pharynx, larynx and visceral organs. It contains more afferent than efferent nerve fibres and projects from the medulla oblongata in the brain stem to the colon.

Toll-like receptor

Highly conserved membrane spanning receptor that recognizes pathogenic molecules that are distinct from host antigens (collectively referred to as pathogen-associated molecular patterns).

Circumventricular organs

Structures that surround the brain ventricles and are devoid of a functional blood–brain barrier because of fenestrated capillaries.

Blood–brain barrier

A series of structures that limit the penetration and diffusion of circulating water-soluble substances into the brain and include tight junctions between endothelial cells of brain capillaries, a dense network of astrocytes, a reduced volume of extracellular milieu and efflux pumps.

Volume diffusion

A form of neurotransmission that involves the diffusion in the extracellular space of neurotransmitters that are normally released from neurons. Volume diffusion permits neurotransmitters and cytokines to reach extrasynaptic receptors.


The tissue of an organ, in this case the brain, that supports its functions and is distinct from supporting and connective tissue.

Anti-inflammatory cytokines

Together with specific cytokine inhibitors and soluble cytokine receptors, these are immunoregulatory molecules that down-regulate the pro-inflammatory cytokine response.

Innate immune system

Part of the immune system that is responsible for natural immunity and is geared toward efficiently recognizing pathogenic molecules independently of any prior exposure.

Acute-phase response

The reaction that develops in response to an injury. It is mediated by pro-inflammatory cytokines and is characterized by a local response (inflammation) and a systemic component, which includes production of acute phase proteins by hepatocytes, fever and profound changes in lipid, protein and carbohydrate metabolism.


This term refers to phenomena that are visceral and controlled by the autonomic nervous system. In the case of depression, neurovegetative symptoms include sleep disturbances, change in appetite and decreased energy.

Depression-like behaviour

Behaviour displayed by laboratory animals that mimics some features of clinical depression. These include, among others, helplessness and anhedonia. Depression-like behaviour is normally alleviated by antidepressant drugs.

Glucocorticoid receptor resistance

This occurs despite normal or excessive concentrations of glucocorticoids. It is sometimes caused by loss-of-function mutations in the glucocorticoid receptor and, more commonly, by events that occur during chronic inflammation, ultimately leading to a reduction in the ability of glucocorticoids to translocate into the nucleus.

Psychomotor retardation

A generalized slowing of physical and mental activity, frequently occurring as a symptom of severe depression.


The presence of one or more diseases in addition to a primary disease.

Illness behaviour

In health psychology, illness behaviour refers to any behaviour undertaken by an individual who feels ill in order to relieve that experience and to better understand the meaning of disease symptoms. It is profoundly influenced by the social context and psychological factors, and manifests itself by denial or amplification of symptoms, attributional processes, a search for medical information, decisions for entering or leaving the health care system, and adherence to treatment.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Dantzer, R., O'Connor, J., Freund, G. et al. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9, 46–56 (2008).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing