Skip to main content

Thank you for visiting nature.com. 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.

  • Review Article
  • Published:

Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens

Nature Reviews Immunology volume 6, pages 318–328 (2006)Cite this article

Key Points

  • Local inflammation includes elements — pain and vasodilation — that are neurally mediated.

  • The systemic acute-phase response includes neurally mediated elements — fever and activation of the central hormonal stress response — that are mediated by the effects of immune factors on the hypothalamus.

  • The cellular and molecular components of the innate immune system provide the first line of defence against invading pathogens, through recognition of pathogen-associated molecular patterns (PAMPs) and initial nonspecific cellular and humoral responses. Immune mediators and cytokines that are subsequently released by the innate immune system rapidly activate nonspecific neural responses that both amplify local immune responses to clear pathogens and trigger systemic neuroendocrine and regional neural responses that eventually return the system to a resting state.

  • These neural responses include systemic hormonal responses (through the hypothalamic–pituitary–adrenal axis); regional neuronal responses (through the sympathetic and parasympathetic nervous systems) that innervate immune organs; and local neuronal responses (through the peripheral nervous system).

  • Immune cells contain the molecular machinery to respond to neural signals, including receptors and signalling pathways. Neurotransmitters (including noradrenaline and acetylcholine), neuropeptides (including opioids, substance P, neuropeptide Y and calcitonin gene-related peptide and hormones (glucocorticoids) alter innate immune-cell function through these molecular mechanisms.

  • The nervous system and innate immune system form a cohesive and integrated early host response to pathogens.

  • This interplay constitutes an important feedback loop that optimizes innate inflammatory responses to invading pathogens. Prolonged or inappropriate central nervous system counter-regulatory responses could predispose the host to excess inflammation (in the context of inadequate hormonal suppression) or uncontrolled infection (in the context of excess or prolonged anti-inflammatory hormonal responses).

Abstract

The central nervous system (CNS) regulates innate immune responses through hormonal and neuronal routes. The neuroendocrine stress response and the sympathetic and parasympathetic nervous systems generally inhibit innate immune responses at systemic and regional levels, whereas the peripheral nervous system tends to amplify local innate immune responses. These systems work together to first activate and amplify local inflammatory responses that contain or eliminate invading pathogens, and subsequently to terminate inflammation and restore host homeostasis. Here, I review these regulatory mechanisms and discuss the evidence indicating that the CNS can be considered as integral to acute-phase inflammatory responses to pathogens as the innate immune system.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Schematic illustration of connections between the nervous and immune systems.
Figure 2: Effects of glucocorticoids on immune-cell populations.
Figure 3: Molecular mechanisms of neurotransmitter and glucocorticoid regulation of cytokine production.
Figure 4: Effects of the peripheral nervous system on immune-cell populations in lymphoid organs.

Similar content being viewed by others

References

  1. Cook, D. N., Pisetsky, D. S. & Schwartz, D. A. Toll-like receptors in the pathogenesis of human disease. Nature Immunol. 5, 975–979 (2004).

    CAS  Google Scholar 

  2. Beutler, B. The Toll-like receptors: analysis by forward genetic methods. Immunogenetics 57, 385–392 (2005). A review of landmark studies on TLRs.

    CAS  PubMed  Google Scholar 

  3. Grimm, M. C. et al. Opiate inhibition of chemokine-induced chemotaxis. Ann. N. Y. Acad. Sci. 840, 9–20 (1998).

    CAS  PubMed  Google Scholar 

  4. Milligan, E. D. et al. Controlling neuropathic pain by adeno-associated virus driven production of the anti-inflammatory cytokine, interleukin-10. Mol. Pain 1, 9 (2005).

    PubMed  PubMed Central  Google Scholar 

  5. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Dhabhar, F. S. Stress-induced enhancement of cell-mediated immunity. Ann. N. Y. Acad. Sci. 840, 359–372 (1998).

    CAS  PubMed  Google Scholar 

  7. Madden, K. S., Felten, S. Y., Felten, D. L., Sundaresan, P. R. & Livnat, S. Sympathetic neural modulation of the immune system. I. Depression of T cell immunity in vivo and vitro following chemical sympathectomy. Brain Behav. Immun. 3, 72–89 (1989).

    CAS  PubMed  Google Scholar 

  8. Amaral, L. A., Diaz-Guilera, A., Moreira, A. A., Goldberger, A. L. & Lipsitz, L. A. Emergence of complex dynamics in a simple model of signalling networks. Proc. Natl Acad. Sci. USA 101, 15551–15555 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Kawashima, K. & Fujii, T. Expression of non-neuronal acetylcholine in lymphocytes and its contribution to the regulation of immune function. Front. Biosci. 9, 2063–2085 (2004). A comprehensive review of non-neuronal cholinergic regulation of immunity.

    CAS  PubMed  Google Scholar 

  10. Maestroni, G. J. & Mazzola, P. Langerhans cells β2-adrenoceptors: role in migration, cytokine production, Th priming and contact hypersensitivity. J. Neuroimmunol. 144, 91–99 (2003).

    CAS  PubMed  Google Scholar 

  11. Woltman, A. M., Massacrier, C., de Fijter, J. W., Caux, C. & van Kooten, C. Corticosteroids prevent generation of CD34+-derived dermal dendritic cells but do not inhibit Langerhans cell development. J. Immunol. 168, 6181–6188 (2002).

    CAS  PubMed  Google Scholar 

  12. Chakravarty, S. & Herkenham, M. Toll-like receptor 4 on nonhematopoietic cells sustains CNS inflammation during endotoxemia, independent of systemic cytokines. J. Neurosci. 25, 1788–1796 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Olson, J. K. & Miller, S. D. Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J. Immunol. 173, 3916–3924 (2004).

    CAS  PubMed  Google Scholar 

  14. Koedel, U. et al. MyD88 is required for mounting a robust host immune response to Streptococcus pneumoniae in the CNS. Brain 127, 1437–1445 (2004).

    PubMed  Google Scholar 

  15. Hench, P. S., Kendall, E. C., Slocumb, C. H. & Polley, H. F. Effects of cortisone acetate and pituitary ACTH on rheumatoid arthritis, rheumatic fever and certain other conditions. Arch. Med. Interna 85, 545–666 (1950).

    CAS  Google Scholar 

  16. Agarwal, S. K. & Marshall, G. D. Jr. Dexamethasone promotes type 2 cytokine production primarily through inhibition of type 1 cytokines. J. Interferon Cytokine Res. 21, 147–155 (2001).

    CAS  PubMed  Google Scholar 

  17. Wick, G. et al. The obese strain of chickens: an animal model with spontaneous autoimmune thyroiditis. Adv. Immunol. 47, 433–500 (1989).

    CAS  PubMed  Google Scholar 

  18. Sternberg, E. M. et al. A central nervous system defect in biosynthesis of corticotropin-releasing hormone is associated with susceptibility to streptococcal cell wall-induced arthritis in Lewis rats. Proc. Natl Acad. Sci. USA 86, 4771–4775 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Crofford, L. J. et al. Hypothalamic-pituitary-adrenal axis perturbations in patients with fibromyalgia. Arthritis Rheum. 37, 1583–1592 (1994).

    CAS  PubMed  Google Scholar 

  20. Johnson, E. O., Vlachoyiannopoulos, P. G., Skopouli, F. N., Tzioufas, A. G. & Moutsopoulos, H. M. Hypofunction of the stress axis in Sjogren's syndrome. J. Rheumatol. 25, 1508–1514 (1998).

    CAS  PubMed  Google Scholar 

  21. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Edwards, C. K., Yunger, L. M., Lorence, R. M., Dantzer, R. & Kelley, K. W. The pituitary gland is required for protection against lethal effects of Salmonella typhimurium. Proc. Natl Acad. Sci. USA 88, 2274–2277 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Ruzek, M. C., Pearce, B. D., Miller, A. H. & Biron, C. A. Endogenous glucocorticoids protect against cytokine-mediated lethality during viral infection. J. Immunol. 162, 3527–3533 (1999).

    CAS  PubMed  Google Scholar 

  24. Gomez, S. A. et al. Endogenous glucocorticoids attenuate Shiga toxin-2-induced toxicity in a mouse model of haemolytic uraemic syndrome. Clin. Exp. Immunol. 131, 217–224 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. MacPhee, I. A., Antoni, F. A. & Mason, D. W. Spontaneous recovery of rats from experimental allergic encephalomyelitis is dependent on regulation of the immune system by endogenous adrenal corticosteroids. J. Exp. Med. 169, 431–445 (1989).

    CAS  PubMed  Google Scholar 

  26. Derijk, R. H. et al. A human glucocorticoid receptor gene variant that increases the stability of the glucocorticoid receptor β-isoform mRNA is associated with rheumatoid arthritis. J. Rheumatol. 28, 2383–2388 (2001).

    CAS  PubMed  Google Scholar 

  27. Leung, D. Y. & Szefler, S. J. Diagnosis and management of steroid-resistant asthma. Clin. Chest Med. 18, 611–625 (1997).

    CAS  PubMed  Google Scholar 

  28. Adcock, I. M. et al. Differences in binding of glucocorticoid receptor to DNA in steroid-resistant asthma. J. Immunol. 154, 3500–3505 (1995).

    CAS  PubMed  Google Scholar 

  29. DeRijk, R. H., Eskandari, F. & Sternberg, E. M. Corticosteroid resistance in a subpopulation of multiple sclerosis patients as measured by ex vivo dexamethasone inhibition of LPS induced IL-6 production. J. Neuroimmunol. 151, 180–188 (2004).

    CAS  PubMed  Google Scholar 

  30. van Winsen, L. M. et al. Sensitivity to glucocorticoids is decreased in relapsing remitting multiple sclerosis. J. Clin. Endocrinol. Metab. 90, 734–740 (2005).

    CAS  PubMed  Google Scholar 

  31. Towers, R. et al. High levels of glucocorticoid receptors in patients with active Crohn's disease may predict steroid resistance. Clin. Exp. Immunol. 141, 357–362 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Ogawa, S. et al. Molecular determinants of crosstalk between nuclear receptors and Toll-like receptors. Cell 122, 707–721 (2005). This study defines nuclear receptor–TLR interactions and clinical implications for glucocorticoid effects in different infections.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Lee, Y. M. et al. A mutation of the glucocorticoid receptor gene in patients with systemic lupus erythematosus. Tohoku J. Exp. Med. 203, 69–76 (2004).

    CAS  PubMed  Google Scholar 

  34. Jiang, T. et al. The phase-shift mutation in the glucocorticoid receptor gene: potential etiologic significance of neuroendocrine mechanisms in lupus nephritis. Clin. Chim. Acta 313, 113–117 (2001).

    CAS  PubMed  Google Scholar 

  35. Mingrone, G. et al. The steroid resistance of Crohn's disease. J. Investig. Med. 47, 319–325 (1999).

    CAS  PubMed  Google Scholar 

  36. Diaz-Borjon, A. et al. Multidrug resistance-1 (MDR-1) in rheumatic autoimmune disorders. Part II: Increased P-glycoprotein activity in lymphocytes from systemic lupus erythematosus patients might affect steroid requirements for disease control. Joint Bone Spine 67, 40–48 (2000).

    CAS  PubMed  Google Scholar 

  37. DeRijk, R. H., Schaaf, M. & de Kloet, E. R. Glucocorticoid receptor variants: clinical implications. J. Steroid Biochem. Mol. Biol. 81, 103–122 (2002). A recent review describing the concept and clinical implications of glucocorticoid resistance.

    CAS  PubMed  Google Scholar 

  38. Oakley, R. H., Sar, M. & Cidlowski, J. A. The human glucocorticoid receptor β isoform. Expression, biochemical properties, and putative function. J. Biol. Chem. 271, 9550–9559 (1996). An interesting study describing the expression, biochemical properties, and function of the glucocorticoid receptor-β in humans.

    CAS  PubMed  Google Scholar 

  39. Leung, D. Y. et al. Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor β. J. Exp. Med. 186, 1567–1574 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Webster, J. I. et al. Anthrax lethal factor represses glucocorticoid and progesterone receptor activity. Proc. Natl Acad. Sci. USA 100, 5706–5711 (2003). The first report of bacterial toxin repressing nuclear hormone receptor transactivation.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Moayeri, M., Webster, J. I., Wiggins, J. F., Leppla, S. H. & Sternberg, E. M. Endocrine perturbation increases susceptibility of mice to anthrax lethal toxin. Infect. Immun. 73, 4238–4244 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Glaser, R. & Kiecolt-Glaser, J. K. Stress-induced immune dysfunction: implications for health. Nature Rev. Immunol. 5, 243–251 (2005). A comprehensive review of mechanisms of stress effects on immunity.

    CAS  Google Scholar 

  43. Vedhara, K. et al. Chronic stress in elderly carers of dementia patients and antibody response to influenza vaccination. Lancet 353, 627–631 (1999).

    CAS  PubMed  Google Scholar 

  44. DeRijk, R. et al. Exercise and circadian rhythm-induced variations in plasma cortisol differentially regulate interleukin-1 β (IL-1 β), IL-6, and tumour necrosis factor-α (TNF α) production in humans: high sensitivity of TNFα and resistance of IL-6. J. Clin. Endocrinol. Metab. 82, 2182–2191 (1997).

    CAS  PubMed  Google Scholar 

  45. Singh, A. et al. Lymphocyte subset responses to exercise and glucocorticoid suppression in healthy men. Med. Sci. Sports Exerc. 28, 822–828 (1996).

    CAS  PubMed  Google Scholar 

  46. Matyszak, M. K., Citterio, S., Rescigno, M. & Ricciardi-Castagnoli, P. Differential effects of corticosteroids during different stages of dendritic cell maturation. Eur. J. Immunol. 30, 1233–1242 (2000).

    CAS  PubMed  Google Scholar 

  47. Moser, M. et al. Glucocorticoids downregulate dendritic cell function in vitro and in vivo. Eur. J. Immunol. 25, 2818–2824 (1995).

    CAS  PubMed  Google Scholar 

  48. Sacedon, R., Vicente, A., Varas, A., Jimenez, E. & Zapata, A. G. Early differentiation of thymic dendritic cells in the absence of glucocorticoids. J. Neuroimmunol. 94, 103–108 (1999).

    CAS  PubMed  Google Scholar 

  49. Ma, W. et al. Dexamethasone inhibits IL-12p40 production in lipopolysaccharide-stimulated human monocytic cells by downregulating the activity of c-Jun N-terminal kinase, the activation protein-1, and NF-κB transcription factors. J. Immunol. 172, 318–330 (2004).

    CAS  PubMed  Google Scholar 

  50. Murray, S. E. et al. Overproduction of corticotropin-releasing hormone blocks germinal center formation: role of corticosterone and impaired follicular dendritic cell networks. J. Neuroimmunol. 156, 31–41 (2004).

    CAS  PubMed  Google Scholar 

  51. Ghosh, S., May, M. J. & Kopp, E. B. NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses. Annu. Rev. Immunol. 16, 225–260 (1998).

    CAS  PubMed  Google Scholar 

  52. Scheinman, R. I., Gualberto, A., Jewell, C. M., Cidlowski, J. A. & Baldwin, A. S. Jr. Characterization of mechanisms involved in transrepression of NF-κ B by activated glucocorticoid receptors. Mol. Cell. Biol. 15, 943–953 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Cronstein, B. N., Kimmel, S. C., Levin, R. I., Martiniuk, F. & Weissmann, G. A mechanism for the antiinflammatory effects of corticosteroids: the glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial-leukocyte adhesion molecule 1 and intercellular adhesion molecule 1. Proc. Natl Acad. Sci. USA 89, 9991–9995 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Atsuta, J., Plitt, J., Bochner, B. S. & Schleimer, R. P. Inhibition of VCAM-1 expression in human bronchial epithelial cells by glucocorticoids. Am. J. Respir. Cell Mol. Biol. 20, 643–650 (1999).

    CAS  PubMed  Google Scholar 

  55. Pitzalis, C. et al. Corticosteroids inhibit lymphocyte binding to endothelium and intercellular adhesion: an additional mechanism for their anti-inflammatory and immunosuppressive effect. J. Immunol. 158, 5007–5016 (1997).

    CAS  PubMed  Google Scholar 

  56. Miyamasu, M. et al. Glucocorticoids inhibit chemokine generation by human eosinophils. J. Allergy Clin. Immunol. 101, 75–83 (1998).

    CAS  PubMed  Google Scholar 

  57. Sewell, W. A., Scurr, L. L., Orphanides, H., Kinder, S. & Ludowyke, R. I. Induction of interleukin-4 and interleukin-5 expression in mast cells is inhibited by glucocorticoids. Clin. Diagn. Lab. Immunol. 5, 18–23 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Richards, D. F., Fernandez, M., Caulfield, J. & Hawrylowicz, C. M. Glucocorticoids drive human CD8+T cell differentiation towards a phenotype with high IL-10 and reduced IL-4, IL-5 and IL-13 production. Eur. J. Immunol. 30, 2344–2354 (2000).

    CAS  PubMed  Google Scholar 

  59. Pype, J. L. et al. Expression of monocyte chemotactic protein (MCP)-1, MCP-2, and MCP-3 by human airway smooth-muscle cells. Modulation by corticosteroids and T-helper 2 cytokines. Am. J. Respir. Cell Mol. Biol. 21, 528–536 (1999).

    CAS  PubMed  Google Scholar 

  60. Homma, T. et al. Corticosteroid and cytokines synergistically enhance Toll-like receptor 2 expression in respiratory epithelial cells. Am. J. Respir. Cell Mol. Biol. 31, 463–469 (2004).

    CAS  PubMed  Google Scholar 

  61. Hermoso, M. A., Matsuguchi, T., Smoak, K. & Cidlowski, J. A. Glucocorticoids and tumour necrosis factor α cooperatively regulate Toll-like receptor 2 gene expression. Mol. Cell Biol. 24, 4743–4756 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Shuto, T. et al. Glucocorticoids synergistically enhance nontypeable Haemophilus influenzae-induced Toll-like receptor 2 expression via a negative cross-talk with p38 MAP kinase. J. Biol. Chem. 277, 17263–17270 (2002).

    CAS  PubMed  Google Scholar 

  63. Bornstein, S. R. et al. Impaired adrenal stress response in Toll-like receptor 2-deficient mice. Proc. Natl Acad. Sci. USA 101, 16695–16700 (2004). This paper provides evidence for a crucial role of TLR2 in adrenal glucocorticoid regulation in septicaemia.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Takeuchi, O., Hoshino, K. & Akira, S. Cutting edge: TLR2-deficient and MyD88-deficient mice are highly susceptible to Staphylococcus aureus infection. J. Immunol. 165, 5392–5396 (2000).

    CAS  PubMed  Google Scholar 

  65. Drennan, M. B. et al. Toll-like receptor 2-deficient mice succumb to Mycobacterium tuberculosis infection. Am. J. Pathol. 164, 49–57 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Silverman, M. N., Miller, A. H., Biron, C. A. & Pearce, B. D. Characterization of an interleukin-6- and adrenocorticotropin-dependent, immune-to-adrenal pathway during viral infection. Endocrinology 145, 3580–3589 (2004).

    CAS  PubMed  Google Scholar 

  67. Sanders, V. M. Interdisciplinary research: noradrenergic regulation of adaptive immunity. Brain Behav. Immun. 11 Oct 2005 (doi: 10.1016/j.bbi.2005.08.005).

  68. Johnson, J. D. et al. Adrenergic receptors mediate stress-induced elevations in extracellular Hsp72. J. Appl. Physiol. 99, 1789–1795 (2005).

    CAS  PubMed  Google Scholar 

  69. 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).

    CAS  PubMed  Google Scholar 

  70. Benschop, R. J. et al. Effects of β-adrenergic blockade on immunologic and cardiovascular changes induced by mental stress. Circulation 89, 762–769 (1994).

    CAS  PubMed  Google Scholar 

  71. Chelmicka-Schorr, E., Checinski, M. & Arnason, B. G. Chemical sympathectomy augments the severity of experimental allergic encephalomyelitis. J. Neuroimmunol. 17, 347–350 (1988).

    CAS  PubMed  Google Scholar 

  72. van der Poll, T., Jansen, J., Endert, E., Sauerwein, H. P. & van Deventer, S. J. Noradrenaline inhibits lipopolysaccharide-induced tumour necrosis factor and interleukin 6 production in human whole blood. Infect. Immun. 62, 2046–2050 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Hasko, G., Elenkov, I. J., Kvetan, V. & Vizi, E. S. Differential effect of selective block of α 2-adrenoreceptors on plasma levels of tumour necrosis factor-α, interleukin-6 and corticosterone induced by bacterial lipopolysaccharide in mice. J. Endocrinol. 144, 457–462 (1995).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  75. Lang, K., Drell, T. L., Niggemann, B., Zanker, K. S. & Entschladen, F. Neurotransmitters regulate the migration and cytotoxicity in natural killer cells. Immunol. Lett. 90, 165–172 (2003).

    CAS  PubMed  Google Scholar 

  76. Straub, R. H. et al. Neurotransmitters of the sympathetic nerve terminal are powerful chemoattractants for monocytes. J. Leukoc. Biol. 67, 553–558 (2000).

    CAS  PubMed  Google Scholar 

  77. Schwarz, H., Villiger, P. M., von Kempis, J. & Lotz, M. Neuropeptide Y is an inducible gene in the human immune system. J. Neuroimmunol. 51, 53–61 (1994).

    CAS  PubMed  Google Scholar 

  78. Larhammar, D. Structural diversity of receptors for neuropeptide Y, peptide YY and pancreatic polypeptide. Regul. Pept. 65, 165–174 (1996).

    CAS  PubMed  Google Scholar 

  79. Straub, R. H. et al. Neuropeptide Y cotransmission with noradrenaline in the sympathetic nerve-macrophage interplay. J. Neurochem. 75, 2464–2471 (2000).

    CAS  PubMed  Google Scholar 

  80. Jetschmann, J. U. et al. Expression and in-vivo modulation of α- and β-adrenoceptors on human natural killer (CD16+) cells. J. Neuroimmunol. 74, 159–164 (1997).

    CAS  PubMed  Google Scholar 

  81. Oberbeck, R. et al. Adrenergic modulation of survival and cellular immune functions during polymicrobial sepsis. Neuroimmunomodulation 11, 214–223 (2004).

    CAS  PubMed  Google Scholar 

  82. Papanicolaou, D. A., Tsigos, C., Oldfield, E. H. & Chrousos, G. P. Acute glucocorticoid deficiency is associated with plasma elevations of interleukin-6: does the latter participate in the symptomatology of the steroid withdrawal syndrome and adrenal insufficiency? J. Clin. Endocrinol. Metab. 81, 2303–2306 (1996).

    CAS  PubMed  Google Scholar 

  83. Metz-Boutigue, M. H., Kieffer, A. E., Goumon, Y. & Aunis, D. Innate immunity: involvement of new neuropeptides. Trends Microbiol. 11, 585–592 (2003).

    CAS  PubMed  Google Scholar 

  84. Tracey, K. J. The inflammatory reflex. Nature 420, 853–859 (2002). A review of antifungal and antibacterial properties of some adrenal peptides.

    CAS  PubMed  Google Scholar 

  85. Laye, S. et al. Subdiaphragmatic vagotomy blocks induction of IL-1 β mRNA in mice brain in response to peripheral LPS. Am. J. Physiol. 268, R1327–R1331 (1995).

    CAS  PubMed  Google Scholar 

  86. Wang, H. et al. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature 421, 384–388 (2003). This paper provides evidence for a role for nicotinic acetylcholine receptor in regulating inflammation.

    CAS  PubMed  Google Scholar 

  87. de Jonge, W. J. et al. Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signalling pathway. Nature Immunol. 6, 844–851 (2005). The mechanism of action of non-pharmacological cholinergic anti-inflammatory intervention (vagus nerve stimulation) is described.

    CAS  Google Scholar 

  88. Czura, C. J. & Tracey, K. J. Autonomic neural regulation of immunity. J. Intern. Med. 257, 156–166 (2005).

    CAS  PubMed  Google Scholar 

  89. van Westerloo, D. J. et al. The cholinergic anti-inflammatory pathway regulates the host response during septic peritonitis. J. Infect. Dis. 191, 2138–2148 (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  91. Yang, H. et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc. Natl Acad. Sci. USA 101, 296–301 (2004).

    CAS  PubMed  Google Scholar 

  92. Chen, G. et al. Suppression of HMGB1 release by stearoyl lysophosphatidylcholine:an additional mechanism for its therapeutic effects in experimental sepsis. J. Lipid Res. 46, 623–627 (2005).

    CAS  PubMed  Google Scholar 

  93. Lotze, M. T. & Tracey, K. J. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nature Rev. Immunol. 5, 331–342 (2005).

    CAS  Google Scholar 

  94. Reyes-Reyna, S., Stegall, T. & Krolick, K. A. Muscle responds to an antibody reactive with the acetylcholine receptor by upregulating monocyte chemoattractant protein 1: a chemokine with the potential to influence the severity and course of experimental myasthenia gravis. J. Immunol. 169, 1579–1586 (2002).

    CAS  PubMed  Google Scholar 

  95. Saeed, R. W. et al. Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation. J. Exp. Med. 201, 1113–1123 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Bulloch, K. et al. Induction of calcitonin gene-related peptide-like immunoreactivity in hippocampal neurons following ischemia: a putative regional modulator of the CNS injury/immune response. Exp. Neurol. 150, 195–205 (1998).

    CAS  PubMed  Google Scholar 

  97. Agelaki, S., Tsatsanis, C., Gravanis, A. & Margioris, A. N. Corticotropin-releasing hormone augments proinflammatory cytokine production from macrophages in vitro and in lipopolysaccharide-induced endotoxin shock in mice. Infect. Immun. 70, 6068–6074 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Cuesta, M. C., Quintero, L., Pons, H. & Suarez-Roca, H. Substance P and calcitonin gene-related peptide increase IL-1β, IL-6 and TNFα secretion from human peripheral blood mononuclear cells. Neurochem. Int. 40, 301–306 (2002).

    CAS  PubMed  Google Scholar 

  99. Green, P. G., Luo, J., Heller, P. H. & Levine, J. D. Further substantiation of a significant role for the sympathetic nervous system in inflammation. Neuroscience 55, 1037–1043 (1993).

    CAS  PubMed  Google Scholar 

  100. Baker, C., Richards, L. J., Dayan, C. M. & Jessop, D. S. Corticotropin-releasing hormone immunoreactivity in human T and B cells and macrophages: co-localization with arginine vasopressin. J. Neuroendocrinol. 15, 1070–1074 (2003).

    CAS  PubMed  Google Scholar 

  101. Webster, E. L. et al. In vivo and in vitro characterization of antalarmin, a nonpeptide corticotropin-releasing hormone (CRH) receptor antagonist: suppression of pituitary ACTH release and peripheral inflammation. Endocrinology 137, 5747–5750 (1996).

    CAS  PubMed  Google Scholar 

  102. Brain, S. D. & Grant, A. D. Vascular actions of calcitonin gene-related peptide and adrenomedullin. Physiol. Rev. 84, 903–934 (2004).

    CAS  PubMed  Google Scholar 

  103. Carucci, J. A. et al. Calcitonin gene-related peptide decreases expression of HLA-DR and CD86 by human dendritic cells and dampens dendritic cell-driven T cell-proliferative responses via the type I calcitonin gene-related peptide receptor. J. Immunol. 164, 3494–3499 (2000).

    CAS  PubMed  Google Scholar 

  104. Tran, M. T., Ritchie, M. H., Lausch, R. N. & Oakes, J. E. Calcitonin gene-related peptide induces IL-8 synthesis in human corneal epithelial cells. J. Immunol. 164, 4307–4312 (2000).

    CAS  PubMed  Google Scholar 

  105. Park, S. H., Hsiao, G. Y. & Huang, G. T. Role of substance P and calcitonin gene-related peptide in the regulation of interleukin-8 and monocyte chemotactic protein-1 expression in human dental pulp. Int. Endod. J. 37, 185–192 (2004).

    CAS  PubMed  Google Scholar 

  106. Millet, I. et al. Inhibition of NF-κB activity and enhancement of apoptosis by the neuropeptide calcitonin gene-related peptide. J. Biol. Chem. 275, 15114–15121 (2000).

    CAS  PubMed  Google Scholar 

  107. Mapp, C. E. et al. The distribution of neurokinin-1 and neurokinin-2 receptors in human central airways. Am. J. Respir. Crit. Care Med. 161, 207–215 (2000).

    CAS  PubMed  Google Scholar 

  108. Lotz, M., Vaughan, J. H. & Carson, D. A. Effect of neuropeptides on production of inflammatory cytokines by human monocytes. Science 241, 1218–1221 (1988).

    CAS  PubMed  Google Scholar 

  109. Croitoru, K., Ernst, P. B., Bienenstock, J., Padol, I. & Stanisz, A. M. Selective modulation of the natural killer activity of murine intestinal intraepithelial leucocytes by the neuropeptide substance P. Immunology 71, 196–201 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Feistritzer, C. et al. Natural killer cell functions mediated by the neuropeptide substance P. Regul. Pept. 116, 119–126 (2003).

    CAS  PubMed  Google Scholar 

  111. Serra, M. C., Calzetti, F., Ceska, M. & Cassatella, M. A. Effect of substance P on superoxide anion and IL-8 production by human PMNL. Immunology 82, 63–69 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Guhl, S., Lee, H. H., Babina, M., Henz, B. M. & Zuberbier, T. Evidence for a restricted rather than generalized stimulatory response of skin-derived human mast cells to substance P. J. Neuroimmunol. 163, 92–101 (2005).

    CAS  PubMed  Google Scholar 

  113. Wang, L., Stanisz, A. M., Wershil, B. K., Galli, S. J. & Perdue, M. H. Substance P induces ion secretion in mouse small intestine through effects on enteric nerves and mast cells. Am. J. Physiol. 269, G85–G92 (1995).

    CAS  PubMed  Google Scholar 

  114. Helme, R. D., Eglezos, A. & Andrews, P. V. The effects of capsaicin denervation on leucocyte and complement components of the inflammatory response. Clin. Exp. Neurol. 24, 207–211 (1987).

    CAS  PubMed  Google Scholar 

  115. Duffy, R. A. Potential therapeutic targets for neurokinin-1 receptor antagonists. Expert Opin. Emerg. Drugs 9, 9–21 (2004).

    CAS  PubMed  Google Scholar 

  116. Kawasaki, H., Nuki, C., Saito, A. & Takasaki, K. Adrenergic modulation of calcitonin gene-related peptide (CGRP)-containing nerve-mediated vasodilation in the rat mesenteric resistance vessel. Brain Res. 506, 287–290 (1990).

    CAS  PubMed  Google Scholar 

  117. Lee, T. H., Lerner, A. B. & Buettner-Janusch, V. The isolation and structure of α- and β-melanocyte-stimulating hormones from monkey pituitary glands. J. Biol. Chem. 236, 1390–1394 (1961).

    CAS  PubMed  Google Scholar 

  118. Roselli-Rehfuss, L. et al. Identification of a receptor for γ melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system. Proc. Natl Acad. Sci. USA 90, 8856–8860 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Lipton, J. M. & Catania, A. Anti-inflammatory actions of the neuroimmunomodulator α-MSH. Immunol. Today 18, 140–145 (1997).

    CAS  PubMed  Google Scholar 

  120. Taylor, A. W. The immunomodulating neuropeptide α-melanocyte-stimulating hormone (α-MSH) suppresses LPS-stimulated TLR4 with IRAK-M in macrophages. J. Neuroimmunol. 162, 43–50 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Mandrika, I., Muceniece, R. & Wikberg, J. E. Effects of melanocortin peptides on lipopolysaccharide/interferon-γ-induced NF-κB DNA binding and nitric oxide production in macrophage-like RAW 264.7 cells: evidence for dual mechanisms of action. Biochem. Pharmacol. 61, 613–621 (2001).

    CAS  PubMed  Google Scholar 

  122. Kiss, M. et al. Effects of the neuropeptides substance P, calcitonin gene-related peptide and α-melanocyte-stimulating hormone on the IL-8/IL-8 receptor system in a cultured human keratinocyte cell line and dermal fibroblasts. Inflammation 23, 557–567 (1999).

    CAS  PubMed  Google Scholar 

  123. van Epps, D. E. & Saland, L. β-endorphin and met-enkephalin stimulate human peripheral blood mononuclear cell chemotaxis. J. Immunol. 132, 3046–3053 (1984).

    CAS  PubMed  Google Scholar 

  124. Zhang, N., Hodge, D., Rogers, T. J. & Oppenheim, J. J. Ca2+-independent protein kinase Cs mediate heterologous desensitization of leukocyte chemokine receptors by opioid receptors. J. Biol. Chem. 278, 12729–12736 (2003). Evidence for crosstalk between opioid receptors and chemokine receptors that are potentially relevant to pain mechanisms and therapy.

    CAS  PubMed  Google Scholar 

  125. Bidlack, J. M. Detection and function of opioid receptors on cells from the immune system. Clin. Diagn. Lab. Immunol. 7, 719–723 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Mellon, R. D. & Bayer, B. M. The effects of morphine, nicotine and epibatidine on lymphocyte activity and hypothalamic-pituitary-adrenal axis responses. J. Pharmacol. Exp. Ther. 288, 635–642 (1999).

    CAS  PubMed  Google Scholar 

  127. Blondel, O. et al. A glia-derived signal regulating neuronal differentiation. J. Neurosci. 20, 8012–8020 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Hernanz, A., Tato, E., De la Fuente, M., de Miguel, E. & Arnalich, F. Differential effects of gastrin-releasing peptide, neuropeptide Y, somatostatin and vasoactive intestinal peptide on interleukin-1 β, interleukin-6 and tumour necrosis factor-α production by whole blood cells from healthy young and old subjects. J. Neuroimmunol. 71, 25–30 (1996).

    CAS  PubMed  Google Scholar 

  129. Martinez, C. et al. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide modulate endotoxin-induced IL-6 production by murine peritoneal macrophages. J. Leukoc. Biol. 63, 591–601 (1998).

    CAS  PubMed  Google Scholar 

  130. Delgado, M., Munoz-Elias, E. J., Gomariz, R. P. & Ganea, D. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide enhance IL-10 production by murine macrophages: in vitro and in vivo studies. J. Immunol. 162, 1707–1716 (1999).

    CAS  PubMed  Google Scholar 

  131. Ganea, D. Regulatory effects of vasoactive intestinal peptide on cytokine production in central and peripheral lymphoid organs. Adv. Neuroimmunol. 6, 61–74 (1996).

    CAS  PubMed  Google Scholar 

  132. Delgado, M. & Ganea, D. Vasoactive intestinal peptide inhibits IL-8 production in human monocytes. Biochem. Biophys. Res. Commun. 301, 825–832 (2003).

    CAS  PubMed  Google Scholar 

  133. Delneste, Y. et al. Vasoactive intestinal peptide synergizes with TNF-α in inducing human dendritic cell maturation. J. Immunol. 163, 3071–3075 (1999).

    CAS  PubMed  Google Scholar 

  134. Gomariz, R. P. et al. Time-course expression of Toll-like receptors 2 and 4 in inflammatory bowel disease and homeostatic effect of VIP. J. Leukoc. Biol. 78, 491–502 (2005).

    CAS  PubMed  Google Scholar 

  135. Delgado, M., Pozo, D. & Ganea, D. The significance of vasoactive intestinal peptide in immunomodulation. Pharmacol. Rev. 56, 249–290 (2004).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  137. Steinman, L. Elaborate interactions between the immune and nervous systems. Nature Immunol. 5, 575–581 (2004).

    CAS  Google Scholar 

  138. Kobilka, B. K. et al. cDNA for the human β2-adrenergic receptor: a protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor. Proc. Natl Acad. Sci. USA 84, 46–50 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Le Tulzo, Y. et al. Hemorrhage increases cytokine expression in lung mononuclear cells in mice: involvement of catecholamines in nuclear factor-κB regulation and cytokine expression. J. Clin. Invest. 99, 1516–1524 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Marques-Deak, A., Cizza, G. & Sternberg, E. Brain-immune interactions and disease susceptibility. Mol. Psychiatry 10, 239–250 (2005).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The author would like to thank H. Gorby and C. Butts for their important contributions to this manuscript.

Author information

Authors and Affiliations

  1. Section on Neuroendocrine Immunology and Behaviour, National Institute of Mental Health, National Institutes of Health, 5625 Fishers Lane, Room 4N-13, MSC-9401, Rockville, 20852, Maryland, USA

    Esther M. Sternberg

Authors
  1. Esther M. Sternberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Esther Sternberg's homepage

Glossary

G-protein-coupled receptors

Cell-surface receptors that are coupled to G-proteins, and have seven transmembrane-spanning domains. The acetylcholine, adrenergic and neuropeptide receptors are all members of this family. Typically, activation of the G-protein-coupled receptor produces a diffusible second messenger that, in turn, triggers various biochemical cascades.

Sympathetic nervous system

(SNS). A division of the autonomic nervous system that consists of fibres projecting from the central nervous system, through ganglia near the spinal cord, to innervate organs such as the heart, lungs, intestine, blood vessels and sweat glands. In general, sympathetic nerves dilate the pupils, constrict peripheral blood vessels and increase heart rate.

Parasympathetic nervous system

A division of the autonomic nervous system that consists of nerve fibres projecting from the central nervous system and sacral portion of the spinal cord, which extend to nerve-cell clusters (ganglia) at specific sites, from which fibres are distributed to blood vessels, glands and other internal organs. Functions of parasympathetic nerves include slowing the heart rate; inducing the secretion of bile, insulin and digestive juices; dilating peripheral blood vessels; and contracting the bronchioles, pupils and oesophagus.

Delayed-type hypersensitivity

A cellular immune response to antigen that develops over 24–72 hours with the infiltration of T cells and monocytes, and depends on the production of T helper 1-cell-specific cytokines.

Noradrenaline

The primary neurotransmitter of the sympathetic nervous system. It is a biogenic amine derived from tyrosine and its metabolite dopamine, which is converted to noradrenaline by the enzyme β-hydroxylase.

Adrenaline

A neurotransmitter of the sympathetic nervous system. It is a biogenic amine derived from tyrosine and its metabolite dopamine, which is converted to adrenaline from noradrenaline by the enzyme phenylethanolamine-N-methyl transferase.

Vagus nerve

The main nerve trunk of the parasympathetic nervous system. It contains both afferent fibres that carry signals from the periphery to the brain, and efferent fibres that carry signals from the brain to the peripheral organs that it innervates.

Pro-opiomelanocortin

(POMC). A 241-amino-acid precursor polypeptide that is synthesized in corticotrophin cells of the pituitary gland. Biologically active peptides derived from POMC include adrenocorticotropic hormone, enkephalins and α-melanocyte-stimulating hormone.

Arcuate nucleus

A collection of neurons in the hypothalamus. It regulates the secretion of hormones through afferent dopaminergic projections to the pituitary.

Paraventricular nucleus

(PVN). A collection of neurons in the hypothalamus that are adjacent to the third ventricle. It contains mainly neurosecretory neurons that secrete corticotrophin-releasing hormone, which stimulates pituitary corticotrophs. In addition, PVN neurons project to the sympathetic brainstem nuclei, parasympathetic brainstem pre-ganglionic neurons and spinal cord.

Endorphins

Endogenous opioid peptides that are produced by the pituitary gland and the hypothalamus. They regulate feelings of pain and hunger.

Enkephalins

Short five-amino-acid polypeptides that are members of endogenous opioid family and that bind to opiate receptors.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sternberg, E. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol 6, 318–328 (2006). https://doi.org/10.1038/nri1810

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1810

This article is cited by

Search

Advanced search

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