The inflammatory reflex


Inflammation is a local, protective response to microbial invasion or injury. It must be fine-tuned and regulated precisely, because deficiencies or excesses of the inflammatory response cause morbidity and shorten lifespan. The discovery that cholinergic neurons inhibit acute inflammation has qualitatively expanded our understanding of how the nervous system modulates immune responses. The nervous system reflexively regulates the inflammatory response in real time, just as it controls heart rate and other vital functions. The opportunity now exists to apply this insight to the treatment of inflammation through selective and reversible 'hard-wired' neural systems.

“The mind has great influence over the body, and maladies often have their origin there.” Molière (1622–1673).

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: The cholinergic anti-inflammatory pathway.
Figure 2: Diffusible versus neural anti-inflammatory pathways.
Figure 3: Wiring of the inflammatory reflex.
Figure 4: Targeting therapies to the cholinergic anti-inflammatory pathway.


  1. 1

    Tracey, K. J. et al. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 330, 662–664 (1987).

  2. 2

    Tracey, K. J. et al. Shock and tissue injury induced by recombinant human cachectin. Science 234, 470–474 (1986).

  3. 3

    Wang, H. et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science 285, 248–251 (1999).

  4. 4

    Tracey, K. J., Vlassara, H. & Cerami, A. Cachectin/tumour necrosis factor. Lancet i, 1122–1126 (1989).

  5. 5

    Tracey, K. J. & Abraham, E. From mouse to man: or what have we learned about cytokine-based anti-inflammatory therapies? Shock 11, 224–225 (1999).

  6. 6

    Andersson, U. et al. High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J. Exp. Med. 192, 565–570 (2000).

  7. 7

    Ulloa, L. et al. Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation. Proc. Natl Acad. Sci. USA 99, 12351–12356 (2002).

  8. 8

    Wang, H., Yang, H., Czura, C. J., Sama, A. E. & Tracey, K. J. HMGB1 as a late mediator of lethal systemic inflammation. Am. J. Respir. Crit Care Med. 164, 1768–1773 (2001).

  9. 9

    Lantz, M., Gullberg, U., Nilsson, E. & Olsson, I. Characterization in vitro of a human tumor necrosis factor-binding protein. A soluble form of a tumor necrosis factor receptor. J. Clin. Invest. 86, 1396 (1990).

  10. 10

    Tsunawaki, S., Sporn, M., Ding, A. & Nathan, C. Deactivation of macrophages by transforming growth factor-β. Nature 334, 260–262 (1988).

  11. 11

    Van der, P. T., Coyle, S. M., Barbosa, K., Braxton, C. C. & Lowry, S. F. Epinephrine inhibits tumor necrosis factor-α and potentiates interleukin 10 production during human endotoxemia. J. Clin. Invest 97, 713–719 (1996).

  12. 12

    Scheinman, R. I., Cogswell, P. C., Lofquist, A. K. & Baldwin, A. S. Jr Role of transcriptional activation of IκBκ in mediation of immunosuppression by glucocorticoids. Science 270, 283–286 (1995).

  13. 13

    Chrousos, G. P. The stress response and immune function: clinical implications. The 1999 Novera H. Spector Lecture. Ann. NY Acad. Sci. 917, 38–67 (2000).

  14. 14

    Madden, K. S., Sanders, V. M. & Felten, D. L. Catecholamine influences and sympathetic neural modulation of immune responsiveness. Annu. Rev. Pharmacol. Toxicol. 35, 417–448 (1995).

  15. 15

    Zhang, M., Borovikova, L. V., Wang, H., Metz, C. & Tracey, K. J. Spermine inhibition of monocyte activation and inflammation. Mol. Med. 5, 595–605 (1999).

  16. 16

    Bertini, R., Bianchi, M. & Ghezzi, P. Adrenalectomy sensitizes mice to the lethal effects of interleukin 1 and tumor necrosis factor. J. Exp. Med. 167, 1708–1712 (1988).

  17. 17

    Butler, L. D. et al. Neuroendocrine regulation of in vivo cytokine production and effects: I. In vivo regulatory networks involving the neuroendocrine system, interleukin-1 and tumor necrosis factor-α. J. Neuroimmunol. 24, 143–153 (1989).

  18. 18

    Bloom, O. et al. Hypophysectomy, high tumor necrosis factor levels, and hemoglobinemia in lethal endotoxemic shock. Shock 10, 395–400 (1998).

  19. 19

    Sternberg, E. M. et al. Inflammatory mediator-induced hypothalamic-pituitary-adrenal axis activation is defective in streptococcal cell wall arthritis-susceptible Lewis rats. Proc. Natl Acad. Sci. USA 86, 2374–2378 (1989).

  20. 20

    Webster, J. I., Tonelli, L. & Sternberg, E. M. Neuroendocrine regulation of immunity. Annu. Rev. Immunol. 20, 125–163 (2002).

  21. 21

    Davidson, N. J. et al. T helper cell 1-type CD4+ T cells, but not B cells, mediate colitis in interleukin 10-deficient mice. J. Exp. Med. 184, 241–251 (1996).

  22. 22

    Johansson, A. C., Hansson, A. S., Nandakumar, K. S., Backlund, J. & Holmdahl, R. IL-10-deficient B10. Q mice develop more severe collagen-induced arthritis, but are protected from arthritis induced with anti-type II collagen antibodies. J. Immunol. 167, 3505–3512 (2001).

  23. 23

    Wexler BC, Dolgin AE & Tryczynski EW . Effects of a bacterial polysaccharide (Piromen) on the pituitary-adrenal axis: adrenal ascorbic acid, cholesterol and histologic alterations. Endocrinology 61, 300–308 (1957).

  24. 24

    Besedovsky, H., Sorkin, E., Felix, D. & Haas, H. Hypothalamic changes during the immune response. Eur. J. Immunol. 7, 323–325 (1977).

  25. 25

    Blalock, J. E. A molecular basis for bidirectional communication between the immune and neuroendocrine systems. Physiol Rev. 69, 1–32 (1989).

  26. 26

    Breder, C. D., Dinarello, C. A. & Saper, C. B. Interleukin-1 immunoreactive innervation of the human hypothalamus. Science 240, 321–324 (1988).

  27. 27

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

  28. 28

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

  29. 29

    Watkins, L. R. & Maier, S. F. Beyond neurons: evidence that immune and glial cells contribute to pathological pain states. Physiol Rev. 82, 981–1011 (2002).

  30. 30

    Borovikova, L. V. et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405, 458–462 (2000).

  31. 31

    Bellinger, D. L., Lorton, D., Lubahn, C. & Felten, D. L. in Psychoneuroimmunology (eds Ader R., Felten, D. L. & Cohen, N) 55–112 (Academic, San Diego, 2001).

  32. 32

    Bernik, T. R. et al. Pharmacological stimulation of the cholinergic antiinflammatory pathway. J. Exp. Med. 195, 781–788 (2002).

  33. 33

    Borovikova, L. V. et al. Role of vagus nerve signaling in CNI-1493-mediated suppression of acute inflammation. Auton. Neurosci. 85, 141–147 (2000).

  34. 34

    Sato, K. Z. et al. Diversity of mRNA expression for muscarinic acetylcholine receptor subtypes and neuronal nicotinic acetylcholine receptor subunits in human mononuclear leukocytes and leukemic cell lines. Neurosci. Lett. 266, 17–20 (1999).

  35. 35

    Sato, E., Koyama, S., Okubo, Y., Kubo, K. & Sekiguchi, M. Acetylcholine stimulates alveolar macrophages to release inflammatory cell chemotactic activity. Am. J. Physiol. 274, L970–L979 (1998).

  36. 36

    Wessler, I., Kirkpatrick, C. J. & Racke, K. Non-neuronal acetylcholine, a locally acting molecule, widely distributed in biological systems: expression and function in humans. Pharmacol. Ther. 77, 59–79 (1998).

  37. 37

    Kawashima, K. & Fujii, T. Extraneuronal cholinergic system in lymphocytes. Pharmacol. Ther. 86, 29–48 (2000).

  38. 38

    Clark, K. B., Naritoku, D. K., Smith, D. C., Browning, R. A. & Jensen, R. A. Enhanced recognition memory following vagus nerve stimulation in human subjects. Nature Neurosci. 2, 94–98 (1999).

  39. 39

    Blalock, J. E. The immune system as a sensory organ. J. Immunol. 132, 1067–1070 (1984).

  40. 40

    Blalock, J. E. Shared ligands and receptors as a molecular mechanism for communication between the immune and neuroendocrine systems. Ann. NY Acad. Sci. 741, 292–298 (1994).

  41. 41

    Goehler, L. E. et al. Vagal immune-to-brain communication: a visceral chemosensory pathway. Auton. Neurosci. 85, 49–59 (2000).

  42. 42

    Hermann, G. E., Emch, G. S., Tovar, C. A. & Rogers, R. C. c-Fos generation in the dorsal vagal complex after systemic endotoxin is not dependent on the vagus nerve. Am. J. Physiol. Regul. Integr. Comp Physiol. 280, R289–R299 (2001).

  43. 43

    Emch, G. S., Hermann, G. E. & Rogers, R. C. TNF-α activates solitary nucleus neurons responsive to gastric distension. Am. J. Physiol. Gastrointest. Liver Physiol. 279, G582–G586 (2000).

  44. 44

    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).

  45. 45

    Watkins, L. R. et al. Blockade of interleukin-1 induced hyperthermia by subdiaphragmatic vagotomy: evidence for vagal mediation of immune-brain communication. Neurosci. Lett. 183, 27–31 (1995).

  46. 46

    Hansen, M. K. et al. Effects of vagotomy on lipopolysaccharide-induced brain interleukin-1β protein in rats. Auton. Neurosci. 85, 119–126 (2000).

  47. 47

    Hansen, M. K., O'Connor, K. A., Goehler, L. E., Watkins, L. R. & Maier, S. F. The contribution of the vagus nerve in interleukin-1β-induced fever is dependent on dose. Am. J. Physiol. Regul. Integr. Comp. Physiol. 280, R929–R934 (2001).

  48. 48

    Romanovsky, A. A. Thermoregulatory manifestations of systemic inflammation: lessons from vagotomy. Auton. Neurosci. Basic Clin. 85, 39–48 (2000).

  49. 49

    Goehler, L. E. et al. Vagal paraganglia bind biotinylated interleukin-1 receptor antagonist: a possible mechanism for immune-to-brain communication. Brain Res. Bull. 43, 357–364 (1997).

  50. 50

    Berthoud, H. R. & Neuhuber, W. L. Functional and chemical anatomy of the afferent vagal system. Auton. Neurosci. 85, 1–17 (2000).

  51. 51

    Gordon, F. J. Effect of nucleus tractus solitarius lesions on fever produced by interleukin-1β. Auton. Neurosci. 85, 102–110 (2000).

  52. 52

    Molina, P. E., Bagby, G. J. & Stahls, P. Hemorrhage alters neuroendocrine, hemodynamic, and compartment-specific TNF responses to LPS. Shock 16, 459–465 (2001).

  53. 53

    Molina, P. E. Noradrenergic inhibition of TNF upregulation in hemorrhagic shock. Neuroimmunomodulation 9, 125–133 (2001).

  54. 54

    Woiciechowsky, C. et al. Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury. Nature Med. 4, 808–813 (1998).

  55. 55

    Koizumi, K., Terui, N., Kollai, M. & Brooks, C. M. Functional significance of coactivation of vagal and sympathetic cardiac nerves. Proc. Natl Acad. Sci. USA 79, 2116–2120 (1982).

  56. 56

    Bianchi, M. et al. Suppression of proinflammatory cytokines in monocytes by a tetravalent guanylhydrazone. J. Exp. Med. 183, 927–936 (1996).

  57. 57

    Bianchi, M. et al. An inhibitor of macrophage arginine transport and nitric oxide production (CNI-1493) prevents acute inflammation and endotoxin lethality. Mol. Med. 1, 254–266 (1995).

  58. 58

    Tracey, K. J. Suppression of TNF and other proinflammatory cytokines by the tetravalent guanylhydrazone CNI-1493. Prog. Clin. Biol. Res. 397, 335–343 (1998).

  59. 59

    Hommes, D. et al. Inhibition of stress-activated MAP kinases induces clinical improvement in moderate to severe Crohn's disease. Gastroenterology 122, 7–14 (2002).

  60. 60

    Tracey, K. J., Czura, C. J. & Ivanova, S. Mind over immunity. FASEB J. 15, 1575–1576 (2001).

  61. 61

    Delgado, H. R. et al. Inhibition of systemic inflammation by central action of the neuropeptide α-melanocyte-stimulating hormone. Neuroimmunomodulation 6, 187–192 (1999).

  62. 62

    Ceriani, G., Macaluso, A., Catania, A. & Lipton, J. M. Central neurogenic antiinflammatory action of α-MSH: modulation of peripheral inflammation induced by cytokines and other mediators of inflammation. Neuroendocrinology 59, 138–143 (1994).

  63. 63

    Catania, A., Arnold, J., Macaluso, A., Hiltz, M. E. & Lipton, J. M. Inhibition of acute inflammation in the periphery by central action of salicylates. Proc. Natl Acad. Sci. USA 88, 8544–8547 (1991).

  64. 64

    Matsumori, A., Ono, K., Nishio, R., Nose, Y. & Sasayama, S. Amiodarone inhibits production of tumor necrosis factor-α by human mononuclear cells: a possible mechanism for its effect in heart failure. Circulation 96, 1386–1389 (1997).

  65. 65

    Dias, D. S. et al. Opposite effects of iv amiodarone on cardiovascular vagal and sympathetic efferent activities in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 283, R543–R548 (2002).

  66. 66

    Arai, I., Hirose, H., Muramatsu, M., Okuyama, S. & Aihara, H. Possible involvement of non-steroidal anti-inflammatory drugs in vagal-mediated gastric acid secretion in rats. Jpn. J. Pharmacol. 37, 91–99 (1985).

  67. 67

    Ben Menachem, E. Vagus nerve stimulation, side effects, and long-term safety. J. Clin. Neurophysiol. 18, 415–418 (2001).

  68. 68

    Schachter, S. C. Vagus nerve stimulation: where are we? Curr. Opin. Neurol. 15, 201–206 (2002).

  69. 69

    Pullan, R. D. et al. Transdermal nicotine for active ulcerative colitis. N. Engl. J. Med. 330, 811–815 (1994).

  70. 70

    Mabley, J. G., Pacher, P., Southan, G. J., Salzman, A. L. & Szabo, C. Nicotine reduces the incidence of type I diabetes in mice. J. Pharmacol. Exp. Ther. 300, 876–881 (2002).

  71. 71

    Metal'nikov, S. a. V. C. Role des reflexes conditionnels dans l'immunite. Ann. Inst. Pasteur 40, 893–900 (1926).

  72. 72

    Madden, K. S. & Felten, D. L. Experimental basis for neural-immune interactions. Physiol Rev. 75, 77–106 (1995).

  73. 73

    Ader R. & Cohen, N. in Psychoneuroimmunology (eds Ader R., Felten, D. L. & Cohen, N) 3–34 (Academic, San Diego, 2001).

  74. 74

    Exton, M. S. et al. Pavlovian conditioning of immune function: animal investigation and the challenge of human application. Behav. Brain Res. 110, 129–141 (2000).

  75. 75

    Black, S. Inhibition of immediate-type hypersensitivity response by direct suggestion under hypnosis. Br. Med. J. 1, 925–929 (1963).

  76. 76

    Zachariae, R. in Psychoneuroimmunology (eds Ader R., Felten, D. L. & Cohen, N.) 133–160 (Academic, San Diego, 2001).

  77. 77

    Noguchi, E. & Hayashi, H. Increases in gastric acidity in response to electroacupuncture stimulation of the hindlimb of anesthetized rats. Jpn. J. Physiol 46, 53–58 (1996).

  78. 78

    Lux, G. et al. Acupuncture inhibits vagal gastric acid secretion stimulated by sham feeding in healthy subjects. Gut 35, 1026–1029 (1994).

  79. 79

    Toussirot, E., Serratrice, G. & Valentin, P. Autonomic nervous system involvement in rheumatoid arthritis. 50 cases. J. Rheumatol. 20, 1508–1514 (1993).

  80. 80

    Tan, J., Akin, S., Beyazova, M., Sepici, V. & Tan, E. Sympathetic skin response and R-R interval variation in rheumatoid arthritis. Two simple tests for the assessment of autonomic function. Am. J. Phys. Med. Rehabil. 72, 196–203 (1993).

  81. 81

    Edmonds, M. E., Jones, T. C., Saunders, W. A. & Sturrock, R. D. Autonomic neuropathy in rheumatoid arthritis. Br. Med. J. 2, 173–175 (1979).

Download references


Supported in part by grants from the National Institutes of Health (National Institute of General Medical Sciences) and the Defense Advanced Research Projects Agency (DARPA). The author is grateful for the thoughtful suggestions from C. Czura, M. Fink, S. Friedman, C. Nathan and B. Sherry.

Author information

Correspondence to Kevin J. Tracey.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Tracey, K. The inflammatory reflex. Nature 420, 853–859 (2002) doi:10.1038/nature01321

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.