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:

Crosstalk between the nociceptive and immune systems in host defence and disease

Nature Reviews Neuroscience volume 16, pages 389–402 (2015)Cite this article

Subjects

Key Points

  • Nociceptors can be activated and eventually sensitized by several pro-inflammatory mediators, including cytokines and chemokines. These mediators cause profound changes in sensory neurons, including mobilization of intracellular calcium, an increase in voltage- or ligand-gated channel expression or function, and alteration of the cellular transcriptional profile.

  • The role of autoantibodies is increasingly being recognized in persistent pain states. Some autoantibodies trigger inflammation and have destructive effects within the sensory nervous system — for instance, neuromyelitis optica and Guillain–Barré syndrome. Some autoantibodies may alter the functional status of the somatosensory system, such as antibodies directed against voltage-gated potassium channel complexes.

  • Nociceptors can affect vascular permeability and modulate the phenotype of immune cells through the release of neuropeptides (such as calcitonin gene-related peptide or substance P) or potentially via the other mediators that are readily released upon activation.

  • Several studies suggest that the interactions between nociceptors and immune cells may have a role in the pathogenesis of several immune-mediated diseases, including arthritis, colitis and psoriasis, as well as upon infection. As a proof of concept, chemical disruption or genetic ablation of nociceptors has a drastic impact on the onset, severity and resolution of several pathological conditions in vivo. Similar conclusions have been suggested by clinical reports.

Abstract

Nociceptors and immune cells both protect the host from potential threats to homeostasis. There is growing evidence for bidirectional signalling between these two systems, and the underlying mechanisms are beginning to be elucidated. An understanding is emerging of how both the adaptive and innate immune systems can activate and sensitize nociceptors, and, reciprocally, how nociceptors modulate immune cells. In this Review, we discuss how these interactions can be adaptive and useful to the organism but also consider when such signalling might be maladaptive and pathophysiological, contributing to immune-mediated diseases and persistent pain states.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: The influence of immune cells on nociceptors.
Figure 2: Immunomodulatory properties of nociceptors.

Similar content being viewed by others

References

  1. Woolf, C. J. & Ma, Q. Nociceptors — noxious stimulus detectors. Neuron 55, 353–364 (2007).

    CAS  PubMed  Google Scholar 

  2. Ren, K. & Dubner, R. Interactions between the immune and nervous systems in pain. Nat. Med. 16, 1267–1276 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Calvo, M., Dawes, J. M. & Bennett, D. L. The role of the immune system in the generation of neuropathic pain. Lancet Neurol. 11, 629–642 (2012). A review of the clinical literature relating to influence of the immune system on neuropathic pain states.

    CAS  PubMed  Google Scholar 

  4. von Hehn, C. A., Baron, R. & Woolf, C. J. Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron 73, 638–652 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Marchand, F., Perretti, M. & McMahon, S. B. Role of the immune system in chronic pain. Nat. Rev. Neurosci. 6, 521–532 (2005).

    CAS  PubMed  Google Scholar 

  6. Scholz, J. & Woolf, C. J. The neuropathic pain triad: neurons, immune cells and glia. Nat. Neurosci. 10, 1361–1368 (2007).

    CAS  PubMed  Google Scholar 

  7. Caroleo, M. C., Costa, N., Bracci-Laudiero, L. & Aloe, L. Human monocyte/macrophages activate by exposure to LPS overexpress NGF and NGF receptors. J. Neuroimmunol. 113, 193–201 (2001).

    CAS  PubMed  Google Scholar 

  8. Leon, A. et al. Mast cells synthesize, store, and release nerve growth factor. Proc. Natl Acad. Sci. USA 91, 3739–3743 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Vega, J. A., Garcia-Suarez, O., Hannestad, J., Perez-Perez, M. & Germana, A. Neurotrophins and the immune system. J. Anat. 203, 1–19 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Lane, N. E. et al. Tanezumab for the treatment of pain from osteoarthritis of the knee. N. Engl. J. Med. 363, 1521–1531 (2010). The first demonstration of the clinical importance of the pro-inflammatory mediator NGF in persistent pain states.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Austin, P. J. & Moalem-Taylor, G. The neuro-immune balance in neuropathic pain: involvement of inflammatory immune cells, immune-like glial cells and cytokines. J. Neuroimmunol. 229, 26–50 (2010).

    CAS  PubMed  Google Scholar 

  12. Miller, R. J., Jung, H., Bhangoo, S. K. & White, F. A. Cytokine and chemokine regulation of sensory neuron function. Handb. Exp. Pharmacol. 194, 417–449 (2009).

    CAS  Google Scholar 

  13. Miller, R. E., Miller, R. J. & Malfait, A. M. Osteoarthritis joint pain: the cytokine connection. Cytokine 70, 185–193 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Clark, A. K., Old, E. A. & Malcangio, M. Neuropathic pain and cytokines: current perspectives. J. Pain Res. 6, 803–814 (2013).

    PubMed  PubMed Central  Google Scholar 

  15. Dawes, J. M. & McMahon, S. B. Chemokines as peripheral pain mediators. Neurosci. Lett. 557, 1–8 (2013).

    CAS  PubMed  Google Scholar 

  16. Ji, R. R., Xu, Z. Z. & Gao, Y. J. Emerging targets in neuroinflammation-driven chronic pain. Nat. Rev. Drug Discov. 13, 533–548 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Kalliomaki, J. et al. A randomized, double-blind, placebo-controlled trial of a chemokine receptor 2 (CCR2) antagonist in posttraumatic neuralgia. Pain 154, 761–767 (2013).

    PubMed  Google Scholar 

  18. Oh, S. B. et al. Chemokines and glycoprotein120 produce pain hypersensitivity by directly exciting primary nociceptive neurons. J. Neurosci. 21, 5027–5035 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Binshtok, A. M. et al. Nociceptors are interleukin-1β sensors. J. Neurosci. 28, 14062–14073 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Jin, X. & Gereau, R. W. Acute p38-mediated modulation of tetrodotoxin-resistant sodium channels in mouse sensory neurons by tumor necrosis factor-α. J. Neurosci. 26, 246–255 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang, J. G. et al. The chemokine CXCL1/growth related oncogene increases sodium currents and neuronal excitability in small diameter sensory neurons. Mol. Pain 4, 38 (2008).

    PubMed  PubMed Central  Google Scholar 

  22. Pezet, S. & McMahon, S. B. Neurotrophins: mediators and modulators of pain. Annu. Rev. Neurosci. 29, 507–538 (2006).

    CAS  PubMed  Google Scholar 

  23. Salter, M. W. & Beggs, S. Sublime microglia: expanding roles for the guardians of the CNS. Cell 158, 15–24 (2014). This paper reviews the preclinical data supporting the role of microglia in pain states.

    CAS  PubMed  Google Scholar 

  24. Calvo, M. & Bennett, D. L. The mechanisms of microgliosis and pain following peripheral nerve injury. Exp. Neurol. 234, 271–282 (2012).

    CAS  PubMed  Google Scholar 

  25. Tsuda, M., Masuda, T., Tozaki-Saitoh, H. & Inoue, K. Microglial regulation of neuropathic pain. J. Pharmacol. Sci. 121, 89–94 (2013).

    CAS  PubMed  Google Scholar 

  26. Vincent, A., Bien, C. G., Irani, S. R. & Waters, P. Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol. 10, 759–772 (2011). This review discusses the evidence relating to autoantibodies and CNS disorders.

    CAS  PubMed  Google Scholar 

  27. Willison, H. J. & Goodyear, C. S. Glycolipid antigens and autoantibodies in autoimmune neuropathies. Trends Immunol. 34, 453–459 (2013).

    CAS  PubMed  Google Scholar 

  28. Kaida, K. & Kusunoki, S. Antibodies to gangliosides and ganglioside complexes in Guillain–Barré syndrome and Fisher syndrome: mini-review. J. Neuroimmunol. 223, 5–12 (2010).

    CAS  PubMed  Google Scholar 

  29. Rinaldi, S. et al. Antibodies to heteromeric glycolipid complexes in Guillain-Barré syndrome. PLoS ONE 8, e82337 (2013).

    PubMed  PubMed Central  Google Scholar 

  30. Moulin, D. E., Hagen, N., Feasby, T. E., Amireh, R. & Hahn, A. Pain in Guillain–Barré syndrome. Neurology 48, 328–331 (1997).

    CAS  PubMed  Google Scholar 

  31. Guillain, G., Barré, J. & Strohl, A. Sur un syndrome de radiculo-nevrite avec hyperalbuminose du liquide cephalorachidien sans reaction cellulaire. Remarques sur les characteres clinique et graphique des reflexes tendinaux. Bull. Mem. Soc. Med. Hopitaux Paris 40, 1462–1470 (in French) (1916).

    Google Scholar 

  32. Xiao, W. H., Yu, A. L. & Sorkin, L. S. Electrophysiological characteristics of primary afferent fibers after systemic administration of anti-GD2 ganglioside antibody. Pain 69, 145–151 (1997).

    CAS  PubMed  Google Scholar 

  33. Ohsawa, T., Miyatake, T. & Yuki, N. Anti-B-series ganglioside-recognizing autoantibodies in an acute sensory neuropathy patient cause cell death of rat dorsal root ganglion neurons. Neurosci. Lett. 157, 167–170 (1993).

    CAS  PubMed  Google Scholar 

  34. Melnick, S. C. Thirty-eight cases of the Guillain–Barré syndrome: an immunological study. BMJ 1, 368–373 (1963).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Wallace, V. C., Cottrell, D. F., Brophy, P. J. & Fleetwood-Walker, S. M. Focal lysolecithin-induced demyelination of peripheral afferents results in neuropathic pain behavior that is attenuated by cannabinoids. J. Neurosci. 23, 3221–3233 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Ruts, L. et al. Unmyelinated and myelinated skin nerve damage in Guillain–Barré syndrome: correlation with pain and recovery. Pain 153, 399–409 (2012).

    CAS  PubMed  Google Scholar 

  37. Pan, C. L. et al. Cutaneous innervation in Guillain–Barré syndrome: pathology and clinical correlations. Brain 126, 386–397 (2003).

    PubMed  Google Scholar 

  38. Wingerchuk, D. M., Lennon, V. A., Lucchinetti, C. F., Pittock, S. J. & Weinshenker, B. G. The spectrum of neuromyelitis optica. Lancet Neurol. 6, 805–815 (2007).

    CAS  PubMed  Google Scholar 

  39. Kanamori, Y. et al. Pain in neuromyelitis optica and its effect on quality of life: a cross-sectional study. Neurology 77, 652–658 (2011).

    CAS  PubMed  Google Scholar 

  40. Lennon, V. A., Kryzer, T. J., Pittock, S. J., Verkman, A. S. & Hinson, S. R. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J. Exp. Med. 202, 473–477 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Hinson, S. R. et al. Molecular outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in astrocytes. Proc. Natl Acad. Sci. USA 109, 1245–1250 (2012).

    CAS  PubMed  Google Scholar 

  42. Howe, C. L. et al. Neuromyelitis optica IgG stimulates an immunological response in rat astrocyte cultures. Glia 62, 692–708 (2014).

    PubMed  PubMed Central  Google Scholar 

  43. Ji, R. R., Berta, T. & Nedergaard, M. Glia and pain: is chronic pain a gliopathy? Pain 154, S10–S28 (2013).

    PubMed  PubMed Central  Google Scholar 

  44. Christopherson, K. S. et al. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120, 421–433 (2005).

    CAS  PubMed  Google Scholar 

  45. Hinson, S. R. et al. Aquaporin-4-binding autoantibodies in patients with neuromyelitis optica impair glutamate transport by down-regulating EAAT2. J. Exp. Med. 205, 2473–2481 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Albrecht, J., Sidoryk-Wegrzynowicz, M., Zielinska, M. & Aschner, M. Roles of glutamine in neurotransmission. Neuron Glia Biol. 6, 263–276 (2010).

    PubMed  Google Scholar 

  47. Marinus, J. et al. Clinical features and pathophysiology of complex regional pain syndrome. Lancet Neurol. 10, 637–648 (2011).

    PubMed  PubMed Central  Google Scholar 

  48. Kohr, D. et al. Autoimmunity against the β2 adrenergic receptor and muscarinic-2 receptor in complex regional pain syndrome. Pain 152, 2690–2700 (2011).

    CAS  PubMed  Google Scholar 

  49. Dubuis, E. et al. Longstanding complex regional pain syndrome is associated with activating autoantibodies against α-1a adrenoceptors. Pain 155, 2408–2417 (2014). This paper includes a demonstration of autoantibody generation in some patients with chronic pain.

    CAS  PubMed  Google Scholar 

  50. Tekus, V. et al. A CRPS-IgG-transfer-trauma model reproducing inflammatory and positive sensory signs associated with complex regional pain syndrome. Pain 155, 299–308 (2014).

    CAS  PubMed  Google Scholar 

  51. Li, W. W. et al. Autoimmunity contributes to nociceptive sensitization in a mouse model of complex regional pain syndrome. Pain 155, 2377–2389 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Irani, S. R. et al. Morvan syndrome: clinical and serological observations in 29 cases. Ann. Neurol. 72, 241–255 (2012).

    PubMed  Google Scholar 

  53. Klein, C. J., Lennon, V. A., Aston, P. A., McKeon, A. & Pittock, S. J. Chronic pain as a manifestation of potassium channel-complex autoimmunity. Neurology 79, 1136–1144 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Poliak, S. et al. Juxtaparanodal clustering of Shaker-like K+ channels in myelinated axons depends on Caspr2 and TAG-1. J. Cell Biol. 162, 1149–1160 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Gold, M. S., Shuster, M. J. & Levine, J. D. Characterization of six voltage-gated K+ currents in adult rat sensory neurons. J. Neurophysiol. 75, 2629–2646 (1996).

    CAS  PubMed  Google Scholar 

  56. Schulte, U. et al. The epilepsy-linked Lgi1 protein assembles into presynaptic Kv1 channels and inhibits inactivation by Kvβ1. Neuron 49, 697–706 (2006).

    CAS  PubMed  Google Scholar 

  57. Goebel, A. et al. Intravenous immunoglobulin treatment of the complex regional pain syndrome: a randomized trial. Ann. Intern. Med. 152, 152–158 (2010).

    PubMed  Google Scholar 

  58. Andoh, T. & Kuraishi, Y. Direct action of immunoglobulin G on primary sensory neurons through Fc gamma receptor I. FASEB J. 18, 182–184 (2004). This paper includes a demonstration that nociceptors can express receptors for immunoglobulins.

    CAS  PubMed  Google Scholar 

  59. Harada, N., Zhao, J., Kurihara, H., Nakagata, N. & Okajima, K. Stimulation of FcγRI on primary sensory neurons increases insulin-like growth factor-I production, thereby reducing reperfusion-induced renal injury in mice. J. Immunol. 185, 1303–1310 (2010); retraction 187, 3448 (2011).

    CAS  PubMed  Google Scholar 

  60. Procaccini, C., Pucino, V., De Rosa, V., Marone, G. & Matarese, G. Neuro-endocrine networks controlling immune system in health and disease. Front. Immunol. 5, 143 (2014).

    PubMed  PubMed Central  Google Scholar 

  61. Belvisi, M. G. Overview of the innervation of the lung. Curr. Opin. Pharmacol. 2, 211–215 (2002).

    CAS  PubMed  Google Scholar 

  62. Brierley, S. M., Jones, R. C. W., Gebhart, G. F. & Blackshaw, L. A. Splanchnic and pelvic mechanosensory afferents signal different qualities of colonic stimuli in mice. Gastroenterology 127, 166–178 (2004).

    PubMed  Google Scholar 

  63. Oaklander, A. L. & Siegel, S. M. Cutaneous innervation: form and function. J. Am. Acad. Dermatol. 53, 1027–1037 (2005).

    PubMed  Google Scholar 

  64. Olofsson, P. S., Rosas-Ballina, M., Levine, Y. A. & Tracey, K. J. Rethinking inflammation: neural circuits in the regulation of immunity. Immunol. Rev. 248, 188–204 (2012). This review discusses the effects of the sympathetic nervous system on immune function.

    PubMed  PubMed Central  Google Scholar 

  65. Andersson, U. & Tracey, K. J. Neural reflexes in inflammation and immunity. J. Exp. Med. 209, 1057–1068 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Tracey, K. J. Reflex control of immunity. Nat. Rev. Immunol. 9, 418–428 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Edvinsson, L., Ekman, R., Jansen, I., McCulloch, J. & Uddman, R. Calcitonin gene-related peptide and cerebral blood vessels: distribution and vasomotor effects. J. Cereb. Blood Flow Metab. 7, 720–728 (1987).

    CAS  PubMed  Google Scholar 

  68. Brain, S. D. & Williams, T. J. Interactions between the tachykinins and calcitonin gene-related peptide lead to the modulation of oedema formation and blood flow in rat skin. Br. J. Pharmacol. 97, 77–82 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Thacker, M. A. et al. CCL2 is a key mediator of microglia activation in neuropathic pain states. Eur. J. Pain 13, 263–272 (2009).

    CAS  PubMed  Google Scholar 

  70. Pettersson, L. M., Geremia, N. M., Ying, Z. & Verge, V. M. Injury-associated PACAP expression in rat sensory and motor neurons is induced by endogenous BDNF. PLoS ONE 9, e100730 (2014).

    PubMed  PubMed Central  Google Scholar 

  71. Barbara, G. et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 126, 693–702 (2004).

    PubMed  Google Scholar 

  72. Hosoi, J. et al. Regulation of Langerhans cell function by nerves containing calcitonin gene-related peptide. Nature 363, 159–163 (1993).

    CAS  PubMed  Google Scholar 

  73. Riol-Blanco, L. et al. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature 510, 157–161 (2014). This paper reveals the essential role of nociceptors in the development of psoriatic disease.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Naukkarinen, A. et al. Quantitative histochemical analysis of mast cells and sensory nerves in psoriatic skin. J. Pathol. 180, 200–205 (1996).

    CAS  PubMed  Google Scholar 

  75. Roch-Arveiller, M. et al. Tachykinins: effects on motility and metabolism of rat polymorphonuclear leucocytes. Pharmacology 33, 266–273 (1986).

    CAS  PubMed  Google Scholar 

  76. Carolan, E. J. & Casale, T. B. Effects of neuropeptides on neutrophil migration through noncellular and endothelial barriers. J. Allergy Clin. Immunol. 92, 589–598 (1993).

    CAS  PubMed  Google Scholar 

  77. Sun, J., Ramnath, R. D. & Bhatia, M. Neuropeptide substance P upregulates chemokine and chemokine receptor expression in primary mouse neutrophils. Am. J. Physiol. Cell Physiol. 293, C696–C704 (2007).

    CAS  PubMed  Google Scholar 

  78. Ruff, M. R., Wahl, S. M. & Pert, C. B. Substance P receptor-mediated chemotaxis of human monocytes. Peptides 6 (Suppl. 2), 107–111 (1985).

    CAS  PubMed  Google Scholar 

  79. Hood, V. C., Cruwys, S. C., Urban, L. & Kidd, B. L. Differential role of neurokinin receptors in human lymphocyte and monocyte chemotaxis. Regul. Pept. 96, 17–21 (2000).

    CAS  PubMed  Google Scholar 

  80. Talme, T., Liu, Z. & Sundqvist, K. G. The neuropeptide calcitonin gene-related peptide (CGRP) stimulates T cell migration into collagen matrices. J. Neuroimmunol. 196, 60–66 (2008).

    CAS  PubMed  Google Scholar 

  81. Smith, C. H., Barker, J. N., Morris, R. W., MacDonald, D. M. & Lee, T. H. Neuropeptides induce rapid expression of endothelial cell adhesion molecules and elicit granulocytic infiltration in human skin. J. Immunol. 151, 3274–3282 (1993).

    CAS  PubMed  Google Scholar 

  82. Levite, M., Cahalon, L., Hershkoviz, R., Steinman, L. & Lider, O. Neuropeptides, via specific receptors, regulate T cell adhesion to fibronectin. J. Immunol. 160, 993–1000 (1998).

    CAS  PubMed  Google Scholar 

  83. Vishwanath, R. & Mukherjee, R. Substance P promotes lymphocyte-endothelial cell adhesion preferentially via LFA-1/ICAM-1 interactions. J. Neuroimmunol. 71, 163–171 (1996).

    CAS  PubMed  Google Scholar 

  84. Kulka, M., Sheen, C. H., Tancowny, B. P., Grammer, L. C. & Schleimer, R. P. Neuropeptides activate human mast cell degranulation and chemokine production. Immunology 123, 398–410 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Fox, F. E. et al. Calcitonin gene-related peptide inhibits proliferation and antigen presentation by human peripheral blood mononuclear cells: effects on B7, interleukin 10, and interleukin 12. J. Invest. Dermatol. 108, 43–48 (1997).

    CAS  PubMed  Google Scholar 

  86. Asahina, A., Hosoi, J., Murphy, G. F. & Granstein, R. D. Calcitonin gene-related peptide modulates Langerhans cell antigen-presenting function. Proc. Assoc. Am. Physicians 107, 242–244 (1995).

    CAS  PubMed  Google Scholar 

  87. Teresi, S., Boudard, F. & Bastide, M. Effect of calcitonin gene-related peptide and vasoactive intestinal peptide on murine CD4 and CD8 T cell proliferation. Immunol. Lett. 50, 105–113 (1996).

    CAS  PubMed  Google Scholar 

  88. Payan, D. G., Brewster, D. R. & Goetzl, E. J. Specific stimulation of human T lymphocytes by substance P. J. Immunol. 131, 1613–1615 (1983).

    CAS  PubMed  Google Scholar 

  89. Braun, A., Wiebe, P., Pfeufer, A., Gessner, R. & Renz, H. Differential modulation of human immunoglobulin isotype production by the neuropeptides substance P, NKA and NKB. J. Neuroimmunol. 97, 43–50 (1999).

    CAS  PubMed  Google Scholar 

  90. Delgado, A. V., McManus, A. T. & Chambers, J. P. Production of tumor necrosis factor-alpha, interleukin 1-beta, interleukin 2, and interleukin 6 by rat leukocyte subpopulations after exposure to substance P. Neuropeptides 37, 355–361 (2003).

    CAS  PubMed  Google Scholar 

  91. Pradhan, L., Nabzdyk, C., Andersen, N. D., LoGerfo, F. W. & Veves, A. Inflammation and neuropeptides: the connection in diabetic wound healing. Expert Rev. Mol. Med. 11, e2 (2009).

    PubMed  PubMed Central  Google Scholar 

  92. Gonzalez-Rey, E. et al. Therapeutic effect of vasoactive intestinal peptide on experimental autoimmune encephalomyelitis: down-regulation of inflammatory and autoimmune responses. Am. J. Pathol. 168, 1179–1188 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Mikami, N. et al. Calcitonin gene-related peptide is an important regulator of cutaneous immunity: effect on dendritic cell and T cell functions. J. Immunol. 186, 6886–6893 (2011).

    CAS  PubMed  Google Scholar 

  94. Rochlitzer, S. et al. The neuropeptide calcitonin gene-related peptide affects allergic airway inflammation by modulating dendritic cell function. Clin. Exp. Allergy 41, 1609–1621 (2011).

    CAS  PubMed  Google Scholar 

  95. Levite, M. Nerve-driven immunity: the direct effects of neurotransmitters on T-cell function. Ann. NY Acad. Sci. 917, 307–321 (2000).

    CAS  PubMed  Google Scholar 

  96. Niissalo, S., Hukkanen, M., Imai, S., Tornwall, J. & Konttinen, Y. T. Neuropeptides in experimental and degenerative arthritis. Ann. NY Acad. Sci. 966, 384–399 (2002).

    CAS  PubMed  Google Scholar 

  97. Firestein, G. S. Evolving concepts of rheumatoid arthritis. Nature 423, 356–361 (2003).

    CAS  PubMed  Google Scholar 

  98. Samuel, E. P. The autonomic and somatic innervation of the articular capsule. Anat. Rec. 113, 53–70 (1952).

    CAS  PubMed  Google Scholar 

  99. Marinozzi, G., Ferrante, F., Gaudio, E., Ricci, A. & Amenta, F. Intrinsic innervation of the rat knee joint articular capsule and ligaments. Acta Anat. 141, 8–14 (1991).

    CAS  PubMed  Google Scholar 

  100. Schaible, H. G., Ebersberger, A. & Von Banchet, G. S. Mechanisms of pain in arthritis. Ann. NY Acad. Sci. 966, 343–354 (2002).

    CAS  PubMed  Google Scholar 

  101. McDougall, J. J. Arthritis and pain. Neurogenic origin of joint pain. Arthritis Res. Ther. 8, 220 (2006).

    PubMed  PubMed Central  Google Scholar 

  102. Courtright, L. J. & Kuzell, W. C. Sparing effect of neurological deficit and trauma on the course of adjuvant arthritis in the rat. Ann. Rheum. Dis. 24, 360–368 (1965).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Colpaert, F. C., Donnerer, J. & Lembeck, F. Effects of capsaicin on inflammation and on the substance P content of nervous tissues in rats with adjuvant arthritis. Life Sci. 32, 1827–1834 (1983).

    CAS  PubMed  Google Scholar 

  104. Knodell, R. G., Handwerger, B. S., Morley, J. E., Levine, A. S. & Brown, D. M. Separate influences of insulin and hyperglycemia on hepatic drug metabolism in mice with genetic and chemically induced diabetes mellitus. J. Pharmacol. Exp. Ther. 230, 256–262 (1984).

    CAS  PubMed  Google Scholar 

  105. Ahmed, M. et al. Capsaicin effects on substance P and CGRP in rat adjuvant arthritis. Regul. Pept. 55, 85–102 (1995).

    CAS  PubMed  Google Scholar 

  106. Donaldson, L. F., McQueen, D. S. & Seckl, J. R. Neuropeptide gene expression and capsaicin-sensitive primary afferents: maintenance and spread of adjuvant arthritis in the rat. J. Physiol. 486, 473–482 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Devillier, P., Weill, B., Renoux, M., Menkes, C. & Pradelles, P. Elevated levels of tachykinin-like immunoreactivity in joint fluids from patients with rheumatic inflammatory diseases. N. Engl. J. Med. 314, 1323 (1986).

    CAS  PubMed  Google Scholar 

  108. Larsson, J., Ekblom, A., Henriksson, K., Lundeberg, T. & Theodorsson, E. Concentration of substance P, neurokinin A, calcitonin gene-related peptide, neuropeptide Y and vasoactive intestinal polypeptide in synovial fluid from knee joints in patients suffering from rheumatoid arthritis. Scand. J. Rheumatol. 20, 326–335 (1991).

    CAS  PubMed  Google Scholar 

  109. Watanabe, N. et al. Immunohistochemical co-localization of transient receptor potential vanilloid (TRPV)1 and sensory neuropeptides in the guinea-pig respiratory system. Neuroscience 141, 1533–1543 (2006).

    CAS  PubMed  Google Scholar 

  110. Undem, B. J. & Carr, M. J. The role of nerves in asthma. Curr. Allergy Asthma Rep. 2, 159–165 (2002).

    PubMed  Google Scholar 

  111. Hamid, Q. & Tulic, M. Immunobiology of asthma. Annu. Rev. Physiol. 71, 489–507 (2009).

    CAS  PubMed  Google Scholar 

  112. Wu, Y. et al. Role of transient receptor potential ion channels and evoked levels of neuropeptides in a formaldehyde-induced model of asthma in BALB/c mice. PLoS ONE 8, e62827 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Hox, V. et al. Crucial role of transient receptor potential ankyrin 1 and mast cells in induction of nonallergic airway hyperreactivity in mice. Am. J. Respir. Crit. Care Med. 187, 486–493 (2013).

    CAS  PubMed  Google Scholar 

  114. Elekes, K. et al. Role of capsaicin-sensitive afferents and sensory neuropeptides in endotoxin-induced airway inflammation and consequent bronchial hyperreactivity in the mouse. Regul. Pept. 141, 44–54 (2007).

    CAS  PubMed  Google Scholar 

  115. Trankner, D., Hahne, N., Sugino, K., Hoon, M. A. & Zuker, C. Population of sensory neurons essential for asthmatic hyperreactivity of inflamed airways. Proc. Natl Acad. Sci. USA 111, 11515–11520 (2014). This paper discusses the role of nociceptors in the asthmatic-like disorders.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Locksley, R. M. Asthma and allergic inflammation. Cell 140, 777–783 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Rogerio, A. P., Andrade, E. L. & Calixto, J. B. C-fibers, but not the transient potential receptor vanilloid 1 (TRPV1), play a role in experimental allergic airway inflammation. Eur. J. Pharmacol. 662, 55–62 (2011).

    CAS  PubMed  Google Scholar 

  118. Alessandri, A. L. et al. Mechanisms underlying the inhibitory effects of tachykinin receptor antagonists on eosinophil recruitment in an allergic pleurisy model in mice. Br. J. Pharmacol. 140, 847–854 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Caceres, A. I. et al. A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma. Proc. Natl Acad. Sci. USA 106, 9099–9104 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Joachim, R. A. et al. Upregulation of tumor necrosis factor-α by stress and substance P in a murine model of allergic airway inflammation. Neuroimmunomodulation 13, 43–50 (2006).

    CAS  PubMed  Google Scholar 

  121. Ramalho, R., Soares, R., Couto, N. & Moreira, A. Tachykinin receptors antagonism for asthma: a systematic review. BMC Pulm. Med. 11, 41 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Salvioli, B. et al. Neurology and neuropathology of the pancreatic innervation. JOP 3, 26–33 (2002).

    PubMed  Google Scholar 

  123. Tsui, H., Razavi, R., Chan, Y., Yantha, J. & Dosch, H. M. 'Sensing' autoimmunity in type 1 diabetes. Trends Mol. Med. 13, 405–413 (2007).

    CAS  PubMed  Google Scholar 

  124. Suri, A. & Szallasi, A. The emerging role of TRPV1 in diabetes and obesity. Trends Pharmacol. Sci. 29, 29–36 (2008).

    CAS  PubMed  Google Scholar 

  125. Todd, J. A. Etiology of type 1 diabetes. Immunity 32, 457–467 (2010).

    CAS  PubMed  Google Scholar 

  126. Razavi, R. et al. TRPV1+ sensory neurons control β cell stress and islet inflammation in autoimmune diabetes. Cell 127, 1123–1135 (2006). This paper shows the importance of nociceptors in autoimmune diabetes.

    CAS  PubMed  Google Scholar 

  127. Persson-Sjogren, S., Forsgren, S. & Taljedal, I. B. Peptides and other neuronal markers in transplanted pancreatic islets. Peptides 21, 741–752 (2000).

    CAS  PubMed  Google Scholar 

  128. Khachatryan, A. et al. Targeted expression of the neuropeptide calcitonin gene-related peptide to beta cells prevents diabetes in NOD mice. J. Immunol. 158, 1409–1416 (1997).

    CAS  PubMed  Google Scholar 

  129. Kahn, S. E., Hull, R. L. & Utzschneider, K. M. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444, 840–846 (2006).

    CAS  PubMed  Google Scholar 

  130. Gram, D. X. et al. Sensory nerve desensitization by resiniferatoxin improves glucose tolerance and increases insulin secretion in Zucker diabetic fatty rats and is associated with reduced plasma activity of dipeptidyl peptidase IV. Eur. J. Pharmacol. 509, 211–217 (2005).

    CAS  PubMed  Google Scholar 

  131. Melnyk, A. & Himms-Hagen, J. Resistance to aging-associated obesity in capsaicin-desensitized rats one year after treatment. Obes. Res. 3, 337–344 (1995).

    CAS  PubMed  Google Scholar 

  132. Khor, B., Gardet, A. & Xavier, R. J. Genetics and pathogenesis of inflammatory bowel disease. Nature 474, 307–317 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Brookes, S. J., Spencer, N. J., Costa, M. & Zagorodnyuk, V. P. Extrinsic primary afferent signalling in the gut. Nat. Rev. Gastroenterol. Hepatol. 10, 286–296 (2013).

    CAS  PubMed  Google Scholar 

  134. Engel, M. A., Becker, C., Reeh, P. W. & Neurath, M. F. Role of sensory neurons in colitis: increasing evidence for a neuroimmune link in the gut. Inflamm. Bowel Dis. 17, 1030–1033 (2011).

    PubMed  Google Scholar 

  135. Kihara, N. et al. Vanilloid receptor-1 containing primary sensory neurones mediate dextran sulphate sodium induced colitis in rats. Gut 52, 713–719 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Fujino, K., Takami, Y., de la Fuente, S. G., Ludwig, K. A. & Mantyh, C. R. Inhibition of the vanilloid receptor subtype-1 attenuates TNBS-colitis. J. Gastrointest. Surg. 8, 842–847; discussion 847–848 (2004).

    PubMed  Google Scholar 

  137. Szitter, I. et al. The role of transient receptor potential vanilloid 1 (TRPV1) receptors in dextran sulfate-induced colitis in mice. J. Mol. Neurosci. 42, 80–88 (2010).

    CAS  PubMed  Google Scholar 

  138. Engel, M. A. et al. TRPA1 and substance P mediate colitis in mice. Gastroenterology 141, 1346–1358 (2011). This paper demonstrates the importance of nociceptors in experimental colitis.

    CAS  PubMed  Google Scholar 

  139. Engel, M. A. et al. Opposite effects of substance P and calcitonin gene-related peptide in oxazolone colitis. Dig. Liver Dis. 44, 24–29 (2012).

    CAS  PubMed  Google Scholar 

  140. Gad, M., Pedersen, A. E., Kristensen, N. N., de Felipe, C. & Claesson, M. H. Blockage of the neurokinin 1 receptor and capsaicin-induced ablation of the enteric afferent nerves protect SCID mice against T-cell-induced chronic colitis. Inflamm. Bowel Dis. 15, 1174–1182 (2009).

    PubMed  Google Scholar 

  141. Ramachandran, R. et al. TRPM8 activation attenuates inflammatory responses in mouse models of colitis. Proc. Natl Acad. Sci. USA 110, 7476–7481 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Keranen, U. et al. Changes in substance P-immunoreactive innervation of human colon associated with ulcerative colitis. Dig. Dis. Sci. 40, 2250–2258 (1995).

    CAS  PubMed  Google Scholar 

  143. Koch, T. R., Carney, J. A. & Go, V. L. Distribution and quantitation of gut neuropeptides in normal intestine and inflammatory bowel diseases. Dig. Dis. Sci. 32, 369–376 (1987).

    CAS  PubMed  Google Scholar 

  144. Beresford, L., Orange, O., Bell, E. B. & Miyan, J. A. Nerve fibres are required to evoke a contact sensitivity response in mice. Immunology 111, 118–125 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Scholzen, T. E. et al. Cutaneous allergic contact dermatitis responses are diminished in mice deficient in neurokinin 1 receptors and augmented by neurokinin 2 receptor blockage. FASEB J. 18, 1007–1009 (2004).

    CAS  PubMed  Google Scholar 

  146. Di Meglio, P., Villanova, F. & Nestle, F. O. Psoriasis. Cold Spring Harb. Perspect. Med. 4, a015354 (2014).

    PubMed  PubMed Central  Google Scholar 

  147. van der Fits, L. et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J. Immunol. 182, 5836–5845 (2009).

    CAS  PubMed  Google Scholar 

  148. Flutter, B. & Nestle, F. O. TLRs to cytokines: mechanistic insights from the imiquimod mouse model of psoriasis. Eur. J. Immunol. 43, 3138–3146 (2013).

    CAS  PubMed  Google Scholar 

  149. Ostrowski, S. M., Belkadi, A., Loyd, C. M., Diaconu, D. & Ward, N. L. Cutaneous denervation of psoriasiform mouse skin improves acanthosis and inflammation in a sensory neuropeptide-dependent manner. J. Invest. Dermatol. 131, 1530–1538 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Farber, E. M., Lanigan, S. W. & Boer, J. The role of cutaneous sensory nerves in the maintenance of psoriasis. Int. J. Dermatol. 29, 418–420 (1990).

    CAS  PubMed  Google Scholar 

  151. Joseph, T., Kurian, J., Warwick, D. J. & Friedmann, P. S. Unilateral remission of psoriasis following traumatic nerve palsy. Br. J. Dermatol. 152, 185–186 (2005).

    CAS  PubMed  Google Scholar 

  152. Chiu, I. M. et al. Bacteria activate sensory neurons that modulate pain and inflammation. Nature 501, 52–57 (2013). This paper demonstrates the direct excitatory actions of microbial proteins on nociceptors.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Meseguer, V. et al. TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins. Nat. Commun. 5, 3125 (2014).

    PubMed  Google Scholar 

  154. Marion, E. et al. Mycobacterial toxin induces analgesia in Buruli ulcer by targeting the angiotensin pathways. Cell 157, 1565–1576 (2014).

    CAS  PubMed  Google Scholar 

  155. Augustyniak, D., Nowak, J. & Lundy, F. T. Direct and indirect antimicrobial activities of neuropeptides and their therapeutic potential. Curr. Protein Pept. Sci. 13, 723–738 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Brogden, K. A., Guthmiller, J. M., Salzet, M. & Zasloff, M. The nervous system and innate immunity: the neuropeptide connection. Nat. Immunol. 6, 558–564 (2005).

    CAS  PubMed  Google Scholar 

  157. Ichinose, M. & Sawada, M. Enhancement of phagocytosis by calcitonin gene-related peptide (CGRP) in cultured mouse peritoneal macrophages. Peptides 17, 1405–1414 (1996).

    CAS  PubMed  Google Scholar 

  158. Ahmed, A. A., Wahbi, A. H. & Nordlin, K. Neuropeptides modulate a murine monocyte/macrophage cell line capacity for phagocytosis and killing of Leishmania major parasites. Immunopharmacol. Immunotoxicol. 23, 397–409 (2001).

    CAS  PubMed  Google Scholar 

  159. Gomes, R. N. et al. Calcitonin gene-related peptide inhibits local acute inflammation and protects mice against lethal endotoxemia. Shock 24, 590–594 (2005).

    CAS  PubMed  Google Scholar 

  160. Jusek, G., Reim, D., Tsujikawa, K. & Holzmann, B. Deficiency of the CGRP receptor component RAMP1 attenuates immunosuppression during the early phase of septic peritonitis. Immunobiology 217, 761–767 (2012).

    CAS  PubMed  Google Scholar 

  161. Ho, W. Z. et al. Substance P modulates human immunodeficiency virus replication in human peripheral blood monocyte-derived macrophages. AIDS Res. Hum. Retroviruses 12, 195–198 (1996).

    CAS  PubMed  Google Scholar 

  162. Wang, X. et al. Neurokinin-1 receptor antagonist (aprepitant) inhibits drug-resistant HIV-1 infection of macrophages in vitro. J. Neuroimmune Pharmacol. 2, 42–48 (2007).

    PubMed  Google Scholar 

  163. Hill, R. NK1 (substance P) receptor antagonists — why are they not analgesic in humans? Trends Pharmacol. Sci. 21, 244–246 (2000).

    CAS  PubMed  Google Scholar 

  164. Ho, T. W. et al. Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention. Neurology 83, 958–966 (2014).

    CAS  PubMed  Google Scholar 

  165. Marcus, R. et al. BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia 34, 114–125 (2014).

    PubMed  Google Scholar 

  166. Nakagawa, N., Sano, H. & Iwamoto, I. Substance P induces the expression of intercellular adhesion molecule-1 on vascular endothelial cells and enhances neutrophil transendothelial migration. Peptides 16, 721–725 (1995).

    CAS  PubMed  Google Scholar 

  167. Kuo, H. P., Lin, H. C., Hwang, K. H., Wang, C. H. & Lu, L. C. Lipopolysaccharide enhances substance P-mediated neutrophil adherence to epithelial cells and cytokine release. Am. J. Respir. Crit. Care Med. 162, 1891–1897 (2000).

    CAS  PubMed  Google Scholar 

  168. Perianin, A., Snyderman, R. & Malfroy, B. Substance P primes human neutrophil activation: a mechanism for neurological regulation of inflammation. Biochem. Biophys. Res. Commun. 161, 520–524 (1989).

    CAS  PubMed  Google Scholar 

  169. Dianzani, C. et al. Priming effects of substance P on calcium changes evoked by interleukin-8 in human neutrophils. J. Leukoc. Biol. 69, 1013–1018 (2001).

    CAS  PubMed  Google Scholar 

  170. Serra, M. C., Bazzoni, F., Della Bianca, V., Greskowiak, M. & Rossi, F. Activation of human neutrophils by substance P. Effect on oxidative metabolism, exocytosis, cytosolic Ca2+ concentration and inositol phosphate formation. J. Immunol. 141, 2118–2124 (1988).

    CAS  PubMed  Google Scholar 

  171. Richter, J., Andersson, R., Edvinsson, L. & Gullberg, U. Calcitonin gene-related peptide (CGRP) activates human neutrophils — inhibition by chemotactic peptide antagonist BOC-MLP. Immunology 77, 416–421 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Tanabe, T. et al. Inhibitory effects of calcitonin gene-related peptide on substance-P-induced superoxide production in human neutrophils. Eur. J. Pharmacol. 314, 175–183 (1996).

    CAS  PubMed  Google Scholar 

  173. Folgueras, A. R. et al. Metalloproteinase MT5-MMP is an essential modulator of neuro-immune interactions in thermal pain stimulation. Proc. Natl Acad. Sci. USA 106, 16451–16456 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Feng, G. et al. The protective effects of calcitonin gene-related peptide on gastric mucosa injury after cerebral ischemia reperfusion in rats. Regul. Pept. 160, 121–128 (2010).

    CAS  PubMed  Google Scholar 

  175. Hagermark, O., Hokfelt, T. & Pernow, B. Flare and itch induced by substance P in human skin. J. Invest. Dermatol. 71, 233–235 (1978).

    CAS  PubMed  Google Scholar 

  176. Janiszewski, J., Bienenstock, J. & Blennerhassett, M. G. Picomolar doses of substance P trigger electrical responses in mast cells without degranulation. Am. J. Physiol. 267, C138–C145 (1994).

    CAS  PubMed  Google Scholar 

  177. Tancowny, B. P., Karpov, V., Schleimer, R. P. & Kulka, M. Substance P primes lipoteichoic acid- and Pam3CysSerLys4-mediated activation of human mast cells by up-regulating Toll-like receptor 2. Immunology 131, 220–230 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Azzolina, A., Bongiovanni, A. & Lampiasi, N. Substance P induces TNF-α and IL-6 production through NFκB in peritoneal mast cells. Biochim. Biophys. Acta 1643, 75–83 (2003).

    CAS  PubMed  Google Scholar 

  179. Shanahan, F., Denburg, J. A., Fox, J., Bienenstock, J. & Befus, D. Mast cell heterogeneity: effects of neuroenteric peptides on histamine release. J. Immunol. 135, 1331–1337 (1985).

    CAS  PubMed  Google Scholar 

  180. Ansel, J. C., Brown, J. R., Payan, D. G. & Brown, M. A. Substance P selectively activates TNF-alpha gene expression in murine mast cells. J. Immunol. 150, 4478–4485 (1993).

    CAS  PubMed  Google Scholar 

  181. Nong, Y. H., Titus, R. G., Ribeiro, J. M. & Remold, H. G. Peptides encoded by the calcitonin gene inhibit macrophage function. J. Immunol. 143, 45–49 (1989).

    CAS  PubMed  Google Scholar 

  182. Kavelaars, A. et al. Activation of human monocytes via a non-neurokinin substance P receptor that is coupled to Gi protein, calcium, phospholipase D, MAP kinase, and IL-6 production. J. Immunol. 153, 3691–3699 (1994).

    CAS  PubMed  Google Scholar 

  183. Voedisch, S., Rochlitzer, S., Veres, T. Z., Spies, E. & Braun, A. Neuropeptides control the dynamic behavior of airway mucosal dendritic cells. PLoS ONE 7, e45951 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Mikami, N. et al. Calcitonin gene-related peptide regulates type IV hypersensitivity through dendritic cell functions. PLoS ONE 9, e86367 (2014). This paper demonstrates the importance of the nociceptor neuropeptide CGRP in model systems of skin hypersensitivity.

    PubMed  PubMed Central  Google Scholar 

  185. Ding, W., Stohl, L. L., Wagner, J. A. & Granstein, R. D. Calcitonin gene-related peptide biases Langerhans cells toward Th2-type immunity. J. Immunol. 181, 6020–6026 (2008).

    CAS  PubMed  Google Scholar 

  186. Santoni, G. et al. Expression of substance P and its neurokinin-1 receptor on thymocytes: functional relevance in the regulation of thymocyte apoptosis and proliferation. Neuroimmunomodulation 10, 232–246 (2002).

    CAS  PubMed  Google Scholar 

  187. Cunin, P. et al. The tachykinins substance P and hemokinin-1 favor the generation of human memory Th17 cells by inducing IL-1β, IL-23, and TNF-like 1A expression by monocytes. J. Immunol. 186, 4175–4182 (2011).

    CAS  PubMed  Google Scholar 

  188. Levite, M. Neuropeptides, by direct interaction with T cells, induce cytokine secretion and break the commitment to a distinct T helper phenotype. Proc. Natl Acad. Sci. USA 95, 12544–12549 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Matsuda, R. et al. Suppression of murine experimental autoimmune optic neuritis by mature dendritic cells transfected with calcitonin gene-related peptide gene. Invest. Ophthalmol. Vis. Sci. 53, 5475–5485 (2012).

    CAS  PubMed  Google Scholar 

  190. Keeble, J., Blades, M., Pitzalis, C., Castro da Rocha, F. A. & Brain, S. D. The role of substance P in microvascular responses in murine joint inflammation. Br. J. Pharmacol. 144, 1059–1066 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Sun, W., Wang, L., Zhang, Z., Chen, M. & Wang, X. Intramuscular transfer of naked calcitonin gene-related peptide gene prevents autoimmune diabetes induced by multiple low-dose streptozotocin in C57BL mice. Eur. J. Immunol. 33, 233–242 (2003).

    CAS  PubMed  Google Scholar 

  192. Gram, D. X. et al. Capsaicin-sensitive sensory fibers in the islets of Langerhans contribute to defective insulin secretion in Zucker diabetic rat, an animal model for some aspects of human type 2 diabetes. Eur. J. Neurosci. 25, 213–223 (2007).

    PubMed  Google Scholar 

  193. Takami, Y. et al. Extrinsic surgical denervation ameliorates TNBS-induced colitis in rats. Hepatogastroenterology 56, 682–686 (2009).

    PubMed  Google Scholar 

  194. Sonea, I. M., Palmer, M. V., Akili, D. & Harp, J. A. Treatment with neurokinin-1 receptor antagonist reduces severity of inflammatory bowel disease induced by Cryptosporidium parvum. Clin. Diagn. Lab. Immunol. 9, 333–340 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Liu, B. et al. TRPA1 controls inflammation and pruritogen responses in allergic contact dermatitis. FASEB J. 27, 3549–3563 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Niizeki, H., Kurimoto, I. & Streilein, J. W. A substance P agonist acts as an adjuvant to promote hapten-specific skin immunity. J. Invest. Dermatol. 112, 437–442 (1999).

    CAS  PubMed  Google Scholar 

  197. Ramalho, R. et al. Substance P antagonist improves both obesity and asthma in a mouse model. Allergy 68, 48–54 (2013).

    CAS  PubMed  Google Scholar 

  198. Stucchi, A. F. et al. NK-1 antagonist reduces colonic inflammation and oxidative stress in dextran sulfate-induced colitis in rats. Am. J. Physiol. Gastrointest. Liver Physiol. 279, G1298–G1306 (2000).

    CAS  PubMed  Google Scholar 

  199. Engel, M. A. et al. The proximodistal aggravation of colitis depends on substance P released from TRPV1-expressing sensory neurons. J. Gastroenterol. 47, 256–265 (2012).

    CAS  PubMed  Google Scholar 

  200. Reinshagen, M. et al. Calcitonin gene-related peptide mediates the protective effect of sensory nerves in a model of colonic injury. J. Pharmacol. Exp. Ther. 286, 657–661 (1998).

    CAS  PubMed  Google Scholar 

  201. Bowden, J. J. et al. Sensory denervation by neonatal capsaicin treatment exacerbates Mycoplasma pulmonis infection in rat airways. Am. J. Physiol. 270, L393–L403 (1996).

    CAS  PubMed  Google Scholar 

  202. Fernandes, E. S. et al. TRPV1 deletion enhances local inflammation and accelerates the onset of systemic inflammatory response syndrome. J. Immunol. 188, 5741–5751 (2012).

    CAS  PubMed  Google Scholar 

  203. Castagliuolo, I. et al. Neurokinin-1 (NK-1) receptor is required in Clostridium difficile-induced enteritis. J. Clin. Invest. 101, 1547–1550 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Walters, N., Trunkle, T., Sura, M. & Pascual, D. W. Enhanced immunoglobulin A response and protection against Salmonella enterica serovar Typhimurium in the absence of the substance P receptor. Infect. Immun. 73, 317–324 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank the Wellcome Trust for its support of their work.

Author information

Authors and Affiliations

  1. King's College London, Wolfson Centre for Age-Related Diseases, Guy's Campus, London, SE1 1UL, UK

    Stephen B. McMahon & Federica La Russa

  2. Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, UK

    David L. H. Bennett

Authors
  1. Stephen B. McMahon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Federica La Russa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David L. H. Bennett
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Stephen B. McMahon, Federica La Russa or David L. H. Bennett.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Nociceptors

Sensory neurons that transduce noxious stimuli, thus conveying the presence of actual or potential tissue damage to the CNS.

Macrophages

Resident innate immune cells with patrolling and phagocytic activity.

Mast cells

Resident innate immune cells that contain high levels of secretory granules filled with immuno- and neuromodulatory mediators.

Cytokines

Small proteins that function as messengers between cells and mediate coordinated responses through paracrine and autocrine signalling.

Transient receptor potential V1

(TRPV1). A channel expressed on the surface of neuronal cells that act as sensors for thermal and chemical stimuli.

Autoantibodies

Antibodies with reactivity against self-antigens.

Fc receptors

Receptors with specificity for the tail region of an antibody (Fc region).

Neuropeptide

A small protein-like mediator that is released by neurons of the peripheral nervous system and CNS.

γδ T cells

γδ T cells are a subset of T cells that express a specific T cell receptor that consists of a protein-chain heterodimer containing one γ-chain and one δ-chain.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

McMahon, S., Russa, F. & Bennett, D. Crosstalk between the nociceptive and immune systems in host defence and disease. Nat Rev Neurosci 16, 389–402 (2015). https://doi.org/10.1038/nrn3946

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn3946

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