Reciprocal regulation of the neural and innate immune systems


Innate immune responses are regulated by microorganisms and cell death, as well as by a third class of stress signal from the nervous and endocrine systems. The innate immune system also feeds back, through the production of cytokines, to regulate the function of the central nervous system (CNS), and this has effects on behaviour. These signals provide an extrinsic regulatory circuit that links physiological, social and environmental conditions, as perceived by the CNS, with transcriptional 'decision-making' in leukocytes. CNS-mediated regulation of innate immune responses optimizes total organism fitness and provides new opportunities for therapeutic control of chronic infectious, inflammatory and neuropsychiatric diseases.

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Figure 1: CNS regulation of innate immune response gene programmes.
Figure 2: Multi-circuit control of the innate immune transcriptome.


  1. 1

    Matzinger, P. Friendly and dangerous signals: is the tissue in control? Nature Immunol. 8, 11–13 (2007).

  2. 2

    Glaser, R. & Kiecolt-Glaser, J. K. Stress-induced immune dysfunction: implications for health. Nature Rev. Immunol. 5, 243–251 (2005).

  3. 3

    Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W. & Kelley, K. W. From inflammation to sickness and depression: when the immune system subjugates the brain. Nature Rev. Neurosci. 9, 46–56 (2008).

  4. 4

    McEwen, B. S. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol. Rev. 87, 873–904 (2007).

  5. 5

    Powell, N. D., Mays, J. W., Bailey, M. T., Hanke, M. L. & Sheridan, J. F. Immunogenic dendritic cells primed by social defeat enhance adaptive immunity to influenza A virus. Brain Behav. Immun. 25, 46–52 (2011).

  6. 6

    Cole, S. W., Hawkley, L. C., Arevalo, J. M. & Cacioppo, J. T. Transcript origin analysis identifies antigen-presenting cells as primary targets of socially regulated gene expression in leukocytes. Proc. Natl Acad. Sci. USA 108, 3080–3085 (2011).

  7. 7

    Cohen, S., Janicki-Deverts, D. & Miller, G. E. Psychological stress and disease. JAMA 298, 1685–1687 (2007).

  8. 8

    Amit, I. et al. Unbiased reconstruction of a mammalian transcriptional network mediating pathogen responses. Science 326, 257–263 (2009).

  9. 9

    Decker, T., Muller, M. & Stockinger, S. The yin and yang of type I interferon activity in bacterial infection. Nature Rev. Immunol. 5, 675–687 (2005).

  10. 10

    Finch, C. E. Evolution in health and medicine Sackler colloquium. Evolution of the human lifespan and diseases of aging: roles of infection, inflammation, and nutrition. Proc. Natl Acad. Sci. USA 1, 1718–1724 (2010).

  11. 11

    Sapolsky, R., Rivier, C., Yamamoto, G., Plotsky, P. & Vale, W. Interleukin-1 stimulates the secretion of hypothalamic corticotropin-releasing factor. Science 238, 522–524 (1987).

  12. 12

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

  13. 13

    Besedovsky, H., del Rey, A., Sorkin, E. & Dinarello, C. A. Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science 233, 652–654 (1986).

  14. 14

    Rhen, T. & Cidlowski, J. A. Antiinflammatory action of glucocorticoids — new mechanisms for old drugs. N. Engl. J. Med. 353, 1711–1723 (2005).

  15. 15

    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).

  16. 16

    Cole, S. et al. Computational identification of gene–social environment interaction at the human IL6 locus. Proc. Natl Acad. Sci. USA 107, 5681–5686 (2010).

  17. 17

    Collado-Hidalgo, A., Sung, C. & Cole, S. Adrenergic inhibition of innate anti-viral response: PKA blockade of type I interferon gene transcription mediates catecholamine support for HIV-1 replication. Brain Behav. Immun. 20, 552–563 (2006).

  18. 18

    Nance, D. M. & Sanders, V. M. Autonomic innervation and regulation of the immune system (1987–2007). Brain Behav. Immun. 21, 736–745 (2007).

  19. 19

    Lee, H. J. et al. GATA-3 induces T helper cell type 2 (Th2) cytokine expression and chromatin remodeling in committed Th1 cells. J. Exp. Med. 192, 105–115 (2000).

  20. 20

    Panina-Bordignon, P. et al. β2-agonists prevent Th1 development by selective inhibition of interleukin 12. J. Clin. Invest. 100, 1513–1519 (1997).

  21. 21

    Cole, S. W., Korin, Y. D., Fahey, J. L. & Zack, J. A. Norepinephrine accelerates HIV replication via protein kinase A-dependent effect on cytokine production. J. Immunol. 161, 610–616 (1998).

  22. 22

    Grebe, K. M. et al. Cutting edge: sympathetic nervous system increases proinflammatory cytokines and exacerbates influenza A virus pathogenesis. J. Immunol. 184, 540–544 (2009).

  23. 23

    Cole, S. W. et al. Social regulation of gene expression in human leukocytes. Genome Biol. 8, 1–13 (2007).

  24. 24

    Sloan, E. K. et al. Social stress enhances sympathetic innervation of primate lymph nodes: mechanisms and implications for viral pathogenesis. J. Neurosci. 27, 8857–8865 (2007).

  25. 25

    Kiecolt-Glaser, J. K. et al. Chronic stress and age-related increases in the proinflammatory cytokine IL-6. Proc. Natl Acad. Sci. USA 100, 9090–9095 (2003).

  26. 26

    Miller, G. E. et al. A functional genomic fingerprint of chronic stress in humans: blunted glucocorticoid and increased NF-κB signaling. Biol. Psychiatry 64, 266–272 (2008).

  27. 27

    Pace, T. W. et al. Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am. J. Psychiatry 163, 1630–1633 (2006).

  28. 28

    Bierhaus, A. et al. A mechanism converting psychosocial stress into mononuclear cell activation. Proc. Natl Acad. Sci. USA 100, 1920–1925 (2003).

  29. 29

    Goebel, M. U., Mills, P. J., Irwin, M. R. & Ziegler, M. G. Interleukin-6 and tumor necrosis factor-α production after acute psychological stress, exercise, and infused isoproterenol: differential effects and pathways. Psychosom. Med. 62, 591–598 (2000).

  30. 30

    Bower, J. E. et al. Inflammatory responses to psychological stress in fatigued breast cancer survivors: relationship to glucocorticoids. Brain Behav. Immun. 21, 251–258 (2007).

  31. 31

    Richlin, V. A., Arevalo, J. M., Zack, J. A. & Cole, S. W. Stress-induced enhancement of NF-κB DNA-binding in the peripheral blood leukocyte pool: effects of lymphocyte redistribution. Brain Behav. Immun. 18, 231–237 (2004).

  32. 32

    Miller, G. E. et al. Low early-life social class leaves a biological residue manifested by decreased glucocorticoid and increased proinflammatory signaling. Proc. Natl Acad. Sci. USA 106, 14716–14721 (2009).

  33. 33

    Engler, H., Bailey, M. T., Engler, A. & Sheridan, J. F. Effects of repeated social stress on leukocyte distribution in bone marrow, peripheral blood and spleen. J. Neuroimmunol. 148, 106–115 (2004).

  34. 34

    Wohleb, E. S. et al. β-adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat. J. Neurosci. 31, 6277–6288 (2011).

  35. 35

    Chen, E. et al. Genome-wide transcriptional profiling linked to social class in asthma. Thorax 64, 38–43 (2009).

  36. 36

    Irwin, M. R., Wang, M., Campomayor, C. O., Collado-Hidalgo, A. & Cole, S. Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation. Arch. Intern. Med. 166, 1756–1762 (2006).

  37. 37

    Irwin, M. R. et al. Sleep loss activates cellular inflammatory signaling. Biol. Psychiatry 64, 538–540 (2008).

  38. 38

    Motivala, S. & Irwin, M. R. Sleep and immunity: cytokine pathways linking sleep and health outcomes. Curr. Dir. Psychol. Sci. 16, 21–25 (2007).

  39. 39

    Meier-Ewert, H. K. et al. Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk. J. Am. Coll. Cardiol. 43, 678–683 (2004).

  40. 40

    Irwin, M. R., Carrillo, C. & Olmstead, R. Sleep loss activates cellular markers of inflammation: sex differences. Brain Behav. Immun. 24, 54–57 (2010).

  41. 41

    O'Connor, M. F., Motivala, S. J., Valladares, E. M., Olmstead, R. & Irwin, M. R. Sex differences in monocyte expression of IL-6: role of autonomic mechanisms. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R145–R151 (2007).

  42. 42

    Watkins, L. R. & Maier, S. F. Implications of immune-to-brain communication for sickness and pain. Proc. Natl Acad. Sci. USA 96, 7710–7713 (1999).

  43. 43

    Miller, A. H., Maletic, V. & Raison, C. L. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol. Psychiatry 65, 732–741 (2009).

  44. 44

    Hart, B. L. Biological basis of the behavior of sick animals. Neurosci. Biobehav. Rev. 12, 123–137 (1988).

  45. 45

    Harrison, N. A. et al. Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol. Psychiatry 66, 407–414 (2009).

  46. 46

    Eisenberger, N. I., Inagaki, T. K., Rameson, L. T., Mashal, N. M. & Irwin, M. R. An fMRI study of cytokine-induced depressed mood and social pain: the role of sex differences. Neuroimage 47, 881–890 (2009).

  47. 47

    Eisenberger, N. I. et al. Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biol. Psychiatry 68, 748–754 (2010).

  48. 48

    Gimeno, D. et al. Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study. Psychol. Med. 39, 413–423 (2009).

  49. 49

    Miller, A. H., Ancoli-Israel, S., Bower, J. E., Capuron, L. & Irwin, M. R. Neuroendocrine–immune mechanisms of behavioral comorbidities in patients with cancer. J. Clin. Oncol. 26, 971–982 (2008).

  50. 50

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

  51. 51

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

  52. 52

    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).

  53. 53

    Wong, M. L., Dong, C., Maestre-Mesa, J. & Licinio, J. Polymorphisms in inflammation-related genes are associated with susceptibility to major depression and antidepressant response. Mol. Psychiatry 13, 800–812 (2008).

  54. 54

    Benedetti, F., Lucca, A., Brambilla, F., Colombo, C. & Smeraldi, E. Interleukin-6 serum levels correlate with response to antidepressant sleep deprivation and sleep phase advance. Prog. Neuropsychopharmacol. Biol. Psychiatry 26, 1167–1170 (2002).

  55. 55

    Raison, C. L., Lowry, C. A. & Rook, G. A. Inflammation, sanitation, and consternation: loss of contact with coevolved, tolerogenic microorganisms and the pathophysiology and treatment of major depression. Arch. Gen. Psychiatry 67, 1211–1224 (2010).

  56. 56

    Imeri, L. & Opp, M. R. How (and why) the immune system makes us sleep. Nature Rev. Neurosci. 10, 199–210 (2009).

  57. 57

    Mullington, J. et al. Dose-dependent effects of endotoxin on human sleep. Am. J. Physiol. Regul. Integr. Comp. Physiol. 278, R947–R955 (2000).

  58. 58

    Raison, C. L. et al. Chronic interferon-α administration disrupts sleep continuity and depth in patients with hepatitis C: association with fatigue, motor slowing, and increased evening cortisol. Biol. Psychiatry 68, 942–949 (2010).

  59. 59

    Vgontzas, A. N. et al. Marked decrease in sleepiness in patients with sleep apnea by etanercept, a tumor necrosis factor-α antagonist. J. Clin. Endocrinol. Metab. 89, 4409–4413 (2004).

  60. 60

    Monk, J. P. et al. Assessment of tumor necrosis factor α blockade as an intervention to improve tolerability of dose-intensive chemotherapy in cancer patients. J. Clin. Oncol. 24, 1852–1859 (2006).

  61. 61

    Irwin, M. R., Olmstead, R., Valladares, E. M., Breen, E. C. & Ehlers, C. L. Tumor necrosis factor antagonism normalizes rapid eye movement sleep in alcohol dependence. Biol. Psychiatry 66, 191–195 (2009).

  62. 62

    Dew, M. A. et al. Healthy older adults' sleep predicts all-cause mortality at 4 to 19 years of follow-up. Psychosom. Med. 65, 63–73 (2003).

  63. 63

    Thomas, K. S., Motivala, S., Olmstead, R. & Irwin, M. R. Sleep depth and fatigue: role of cellular inflammatory activation. Brain Behav. Immun. 25, 53–58 (2011).

  64. 64

    Cho, H. J., Seeman, T. E., Bower, J. E., Kiefe, C. I. & Irwin, M. R. Prospective association between C-reactive protein and fatigue in the coronary artery risk development in young adults study. Biol. Psychiatry 66, 871–878 (2009).

  65. 65

    Heesen, C. et al. Fatigue in multiple sclerosis: an example of cytokine mediated sickness behaviour? J. Neurol. Neurosurg. Psychiatry 77, 34–39 (2006).

  66. 66

    Harboe, E. et al. Fatigue in primary Sjogren's syndrome — a link to sickness behaviour in animals? Brain Behav. Immun. 23, 1104–1108 (2009).

  67. 67

    Davis, M. C. et al. Chronic stress and regulation of cellular markers of inflammation in rheumatoid arthritis: implications for fatigue. Brain Behav. Immun. 22, 24–32 (2008).

  68. 68

    Schubert, C., Hong, S., Natarajan, L., Mills, P. J. & Dimsdale, J. E. The association between fatigue and inflammatory marker levels in cancer patients: a quantitative review. Brain Behav. Immun. 21, 413–427 (2007).

  69. 69

    Bower, J. E. et al. Inflammatory biomarkers and fatigue during radiation therapy for breast and prostate cancer. Clin. Cancer Res. 15, 5534–5540 (2009).

  70. 70

    Collado-Hidalgo, A., Bower, J. E., Ganz, P. A., Cole, S. W. & Irwin, M. R. Inflammatory biomarkers for persistent fatigue in breast cancer survivors. Clin. Cancer Res. 12, 2759–2766 (2006).

  71. 71

    Bower, J. E., Ganz, P. A., Irwin, M. R., Arevalo, J. M. & Cole, S. W. Fatigue and gene expression in human leukocytes: increased NF-κB and decreased glucocorticoid signaling in breast cancer survivors with persistent fatigue. Brain Behav. Immun. 25, 147–150 (2011).

  72. 72

    Collado-Hidalgo, A., Bower, J. E., Ganz, P. A., Irwin, M. R. & Cole, S. W. Cytokine gene polymorphisms and fatigue in breast cancer survivors: early findings. Brain Behav. Immun. 22, 1197–1200 (2008).

  73. 73

    Zautra, A. J. et al. Comparison of cognitive behavioral and mindfulness meditation interventions on adaptation to rheumatoid arthritis for patients with and without history of recurrent depression. J. Consult. Clin. Psychol. 76, 408–421 (2008).

  74. 74

    Nicklas, B. J. et al. Exercise training and plasma C-reactive protein and interleukin-6 in elderly people. J. Am. Geriatr. Soc. 56, 2045–2052 (2008).

  75. 75

    Pace, T. W. et al. Effect of compassion meditation on neuroendocrine, innate immune and behavioral responses to psychosocial stress. Psychoneuroendocrinology 34, 87–98 (2009).

  76. 76

    Irwin, M. R. & Olmstead, R. Mitigating cellular inflammation in older adults. Am. J. Geriatr. Psychiatry (in the press).

  77. 77

    Lavretsky, H. et al. Complementary use of Tai Chi Chih augments escitalopram treatment of geriatric depression: a randomized controlled trial. Am. J. Geriatr. Psychiatry 6 Mar 2011 (doi:10.1097/JGP.0b013e31820ee9ef).

  78. 78

    Sloan, E. K. et al. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res. 70, 7042–7052 (2010).

  79. 79

    Idaghdour, Y. et al. Geographical genomics of human leukocyte gene expression variation in southern Morocco. Nature Genet. 42, 62–67 (2010).

  80. 80

    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).

  81. 81

    Cole, S. W. in Complex Systems Science in Biomedicine (eds Deisboeck, T. S. & Kresh, J. Y.) 605–629 (Springer, New York, 2006).

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The authors are supported by grants R01-AG034588, R01-AG026364, R01-CA119159, R01-HL079955, P30-AG028748 and R01-MH091352 (to M.R.I.); grants R01-CA116778, R01-AG033590, R21-CA138687 and P30-AG028748 (to S.W.C.); and the Cousins Center for Psychoneuroimmunology.

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Correspondence to Michael R. Irwin.

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Belonging to the same species.


A class of steroid hormones that are involved in carbohydrate, protein and fat metabolism. These hormones are anti-inflammatory and immunosuppressive.


(HPA). This term refers to a complex set of direct influences and feedback interactions between the hypothalamus, the pituitary gland (a pea-shaped structure located below the hypothalamus) and the adrenal glands (small, conical organs on top of the kidneys).

Non-rapid eye movement sleep

(NREM sleep). The sleep stages 1–3 (previously known as stages 1–4) are collectively referred to as NREM sleep. Rapid eye movement (REM) sleep is not included. There are distinct electroencephalographic and other characteristics seen in each stage, and there is usually little or no eye movement during NREM sleep. Dreaming is rare during NREM sleep, and muscles are not paralyzed as in REM sleep.

Social ecology

A broad range of complex physical and symbolic features of the environment that are created by the presence of conspecifics (including social structures such as cultural systems or socio-economic status), as well as physical processes, such as transmission of communicable diseases, provision of medical care or physical aggression.

Sympathetic nervous system

(SNS). One of three parts of the autonomic nervous system (along with the enteric and parasympathetic systems). The SNS serves to mobilize the body's resources during flight-or-flight stress responses.

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Irwin, M., Cole, S. Reciprocal regulation of the neural and innate immune systems. Nat Rev Immunol 11, 625–632 (2011) doi:10.1038/nri3042

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