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

Nature Reviews Neuroscience

Volumn 16, Issue 7, 2015, Pages 389-402

  Mcmahon, Stephen B ^a   La Russa, Federica ^a   Bennett, David L H ^b  

^a KING'S COLLEGE LONDON   (United Kingdom)

^b UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

AUTOANTIBODY; NEUROPEPTIDE;

ARTHRITIS; ASTHMA; DIABETES MELLITUS; DISEASES; HOST RESISTANCE; HUMAN; IMMUNOCOMPETENT CELL; IMMUNOMODULATION; INFECTION; NEUROMODULATION; NOCICEPTION; NONHUMAN; PAIN; PAIN RECEPTOR; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PSORIASIS; REVIEW; SIGNAL TRANSDUCTION; ADAPTIVE IMMUNITY; ANIMAL; CELLULAR IMMUNITY; HOST RANGE; IMMUNE SYSTEM; IMMUNOLOGY; IMMUNOPATHOLOGY; INNATE IMMUNITY; METABOLISM;

ADAPTIVE IMMUNITY; ANIMALS; HOST SPECIFICITY; HUMANS; IMMUNE SYSTEM; IMMUNE SYSTEM DISEASES; IMMUNITY, CELLULAR; IMMUNITY, INNATE; NOCICEPTORS; PAIN;

EID: 84932105591     PISSN: 1471003X     EISSN: 14710048     Source Type: Journal    
DOI: 10.1038/nrn3946     Document Type: Review

References (204)

1. Woolf, C. J. & Ma, Q. Nociceptors-noxious stimulus detectors. Neuron 55, 353-364 (2007).
2. Ren, K. & Dubner, R. Interactions between the immune and nervous systems in pain. Nat. Med. 16, 1267-1276 (2010).
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).
4. von Hehn, C. A., Baron, R. & Woolf, C. J. Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron 73, 638-652 (2012).
5. Marchand, F., Perretti, M. & McMahon, S. B. Role of the immune system in chronic pain. Nat. Rev. Neurosci. 6, 521-532 (2005).
6. Scholz, J. & Woolf, C. J. The neuropathic pain triad: neurons, immune cells and glia. Nat. Neurosci. 10, 1361-1368 (2007).
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).
8. Leon, A. et al. Mast cells synthesize, store, and release nerve growth factor. Proc. Natl Acad. Sci. USA 91, 3739-3743 (1994).
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).
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).
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).
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).
13. Miller, R. E., Miller, R. J. & Malfait, A. M. Osteoarthritis joint pain: the cytokine connection. Cytokine 70, 185-193 (2014).
14. Clark, A. K., Old, E. A. & Malcangio, M. Neuropathic pain and cytokines: current perspectives. J. Pain Res. 6, 803-814 (2013).
15. Dawes, J. M. & McMahon, S. B. Chemokines as peripheral pain mediators. Neurosci. Lett. 557, 1-8 (2013).
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).
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).
18. Oh, S. B. et al. Chemokines and glycoprotein120 produce pain hypersensitivity by directly exciting primary nociceptive neurons. J. Neurosci. 21, 5027-5035 (2001).
19. Binshtok, A. M. et al. Nociceptors are interleukin-1β sensors. J. Neurosci. 28, 14062-14073 (2008).
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).
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).
22. Pezet, S. & McMahon, S. B. Neurotrophins: mediators and modulators of pain. Annu. Rev. Neurosci. 29, 507-538 (2006).
23. Salter, M. W. & Beggs, S. Sublime microglia: expanding roles for the guardians of the CNS. Cell 158, 15-24 (2014).
24. Calvo, M. & Bennett, D. L. The mechanisms of microgliosis and pain following peripheral nerve injury. Exp. Neurol. 234, 271-282 (2012).
25. Tsuda, M., Masuda, T., Tozaki-Saitoh, H. & Inoue, K. Microglial regulation of neuropathic pain. J. Pharmacol. Sci. 121, 89-94 (2013).
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).
27. Willison, H. J. & Goodyear, C. S. Glycolipid antigens and autoantibodies in autoimmune neuropathies. Trends Immunol. 34, 453-459 (2013).
28. Kaida, K. & Kusunoki, S. Antibodies to gangliosides and ganglioside complexes in Guillain-Barre syndrome and Fisher syndrome: mini-review. J. Neuroimmunol. 223, 5-12 (2010).
29. Rinaldi, S. et al. Antibodies to heteromeric glycolipid complexes in Guillain-Barre syndrome. PLoS ONE 8, e82337 (2013).
30. Moulin, D. E., Hagen, N., Feasby, T. E., Amireh, R. & Hahn, A. Pain in Guillain-Barre syndrome. Neurology 48, 328-331 (1997).
31. Guillain, G., Barre, 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).
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).
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).
34. Melnick, S. C. Thirty-eight cases of the Guillain-Barre syndrome: an immunological study. BMJ 1, 368-373 (1963).
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).
36. Ruts, L. et al. Unmyelinated and myelinated skin nerve damage in Guillain-Barre syndrome: correlation with pain and recovery. Pain 153, 399-409 (2012).
37. Pan, C. L. et al. Cutaneous innervation in Guillain-Barre syndrome: pathology and clinical correlations. Brain 126, 386-397 (2003).
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).
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).
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).
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).
42. Howe, C. L. et al. Neuromyelitis optica IgG stimulates an immunological response in rat astrocyte cultures. Glia 62, 692-708 (2014).
43. Ji, R. R., Berta, T. & Nedergaard, M. Glia and pain: is chronic pain a gliopathy? Pain 154, S10-S28 (2013).
44. Christopherson, K. S. et al. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120, 421-433 (2005).
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).
46. Albrecht, J., Sidoryk-Wegrzynowicz, M., Zielinska, M. & Aschner, M. Roles of glutamine in neurotransmission. Neuron Glia Biol. 6, 263-276 (2010).
47. Marinus, J. et al. Clinical features and pathophysiology of complex regional pain syndrome. Lancet Neurol. 10, 637-648 (2011).
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).
49. Dubuis, E. et al. Longstanding complex regional pain syndrome is associated with activating autoantibodies against α-1a adrenoceptors. Pain 155, 2408-2417 (2014).
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).
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).
52. Irani, S. R. et al. Morvan syndrome: clinical and serological observations in 29 cases. Ann. Neurol. 72, 241-255 (2012).
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).
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).
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).
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).
57. Goebel, A. et al. Intravenous immunoglobulin treatment of the complex regional pain syndrome: a randomized trial. Ann. Intern. Med. 152, 152-158 (2010).
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).
59. Harada, N., Zhao, J., Kurihara, H., Nakagata, N. & Okajima, K. Stimulation of Fc?RI 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).
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).
61. Belvisi, M. G. Overview of the innervation of the lung. Curr. Opin. Pharmacol. 2, 211-215 (2002).
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).
63. Oaklander, A. L. & Siegel, S. M. Cutaneous innervation: form and function. J. Am. Acad. Dermatol. 53, 1027-1037 (2005).
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).
65. Andersson, U. & Tracey, K. J. Neural reflexes in inflammation and immunity. J. Exp. Med. 209, 1057-1068 (2012).
66. Tracey, K. J. Reflex control of immunity. Nat. Rev. Immunol. 9, 418-428 (2009).
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).
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).
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).
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).
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).
72. Hosoi, J. et al. Regulation of Langerhans cell function by nerves containing calcitonin gene-related peptide. Nature 363, 159-163 (1993).
73. Riol-Blanco, L. et al. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature 510, 157-161 (2014).
74. Naukkarinen, A. et al. Quantitative histochemical analysis of mast cells and sensory nerves in psoriatic skin. J. Pathol. 180, 200-205 (1996).
75. Roch-Arveiller, M. et al. Tachykinins: effects on motility and metabolism of rat polymorphonuclear leucocytes. Pharmacology 33, 266-273 (1986).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
95. Levite, M. Nerve-driven immunity: the direct effects of neurotransmitters on T-cell function. Ann. NY Acad. Sci. 917, 307-321 (2000).
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).
97. Firestein, G. S. Evolving concepts of rheumatoid arthritis. Nature 423, 356-361 (2003).
98. Samuel, E. P. The autonomic and somatic innervation of the articular capsule. Anat. Rec. 113, 53-70 (1952).
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).
100. Schaible, H. G., Ebersberger, A. & Von Banchet, G. S. Mechanisms of pain in arthritis. Ann. NY Acad. Sci. 966, 343-354 (2002).
101. McDougall, J. J. Arthritis and pain. Neurogenic origin of joint pain. Arthritis Res. Ther. 8, 220 (2006).
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).
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).
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).
105. Ahmed, M. et al. Capsaicin effects on substance P and CGRP in rat adjuvant arthritis. Regul. Pept. 55, 85-102 (1995).
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).
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).
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).
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).
110. Undem, B. J. & Carr, M. J. The role of nerves in asthma. Curr. Allergy Asthma Rep. 2, 159-165 (2002).
111. Hamid, Q. & Tulic, M. Immunobiology of asthma. Annu. Rev. Physiol. 71, 489-507 (2009).
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).
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).
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).
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).
116. Locksley, R. M. Asthma and allergic inflammation. Cell 140, 777-783 (2010).
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).
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).
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).
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).
121. Ramalho, R., Soares, R., Couto, N. & Moreira, A. Tachykinin receptors antagonism for asthma: a systematic review. BMC Pulm. Med. 11, 41 (2011).
122. Salvioli, B. et al. Neurology and neuropathology of the pancreatic innervation. JOP 3, 26-33 (2002).
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).
124. Suri, A. & Szallasi, A. The emerging role of TRPV1 in diabetes and obesity. Trends Pharmacol. Sci. 29, 29-36 (2008).
125. Todd, J. A. Etiology of type 1 diabetes. Immunity 32, 457-467 (2010).
126. Razavi, R. et al. TRPV1+ sensory neurons control β cell stress and islet inflammation in autoimmune diabetes. Cell 127, 1123-1135 (2006).
127. Persson-Sjogren, S., Forsgren, S. & Taljedal, I. B. Peptides and other neuronal markers in transplanted pancreatic islets. Peptides 21, 741-752 (2000).
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).
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).
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).
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).
132. Khor, B., Gardet, A. & Xavier, R. J. Genetics and pathogenesis of inflammatory bowel disease. Nature 474, 307-317 (2011).
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).
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).
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).
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).
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).
138. Engel, M. A. et al. TRPA1 and substance P mediate colitis in mice. Gastroenterology 141, 1346-1358 (2011).
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).
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).
141. Ramachandran, R. et al. TRPM8 activation attenuates inflammatory responses in mouse models of colitis. Proc. Natl Acad. Sci. USA 110, 7476-7481 (2013).
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).
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).
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).
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).
146. Di Meglio, P., Villanova, F. & Nestle, F. O. Psoriasis. Cold Spring Harb. Perspect. Med. 4, a015354 (2014).
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).
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).
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).
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).
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).
152. Chiu, I. M. et al. Bacteria activate sensory neurons that modulate pain and inflammation. Nature 501, 52-57 (2013).
153. Meseguer, V. et al. TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins. Nat. Commun. 5, 3125 (2014).
154. Marion, E. et al. Mycobacterial toxin induces analgesia in Buruli ulcer by targeting the angiotensin pathways. Cell 157, 1565-1576 (2014).
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).
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).
157. Ichinose, M. & Sawada, M. Enhancement of phagocytosis by calcitonin gene-related peptide (CGRP) in cultured mouse peritoneal macrophages. Peptides 17, 1405-1414 (1996).
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).
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).
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).
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).
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).
163. Hill, R. NK1 (substance P) receptor antagonists-why are they not analgesic in humans? Trends Pharmacol. Sci. 21, 244-246 (2000).
164. Ho, T. W. et al. Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention. Neurology 83, 958-966 (2014).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
175. Hagermark, O., Hokfelt, T. & Pernow, B. Flare and itch induced by substance P in human skin. J. Invest. Dermatol. 71, 233-235 (1978).
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).
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).
178. Azzolina, A., Bongiovanni, A. & Lampiasi, N. Substance P induces TNF-α and IL-6 production through NF?B in peritoneal mast cells. Biochim. Biophys. Acta 1643, 75-83 (2003).
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).
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).
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).
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).
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).
184. Mikami, N. et al. Calcitonin gene-related peptide regulates type IV hypersensitivity through dendritic cell functions. PLoS ONE 9, e86367 (2014).
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).
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).
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).
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).
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).
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).
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).
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).
193. Takami, Y. et al. Extrinsic surgical denervation ameliorates TNBS-induced colitis in rats. Hepatogastroenterology 56, 682-686 (2009).
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).
195. Liu, B. et al. TRPA1 controls inflammation and pruritogen responses in allergic contact dermatitis. FASEB J. 27, 3549-3563 (2013).
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).
197. Ramalho, R. et al. Substance P antagonist improves both obesity and asthma in a mouse model. Allergy 68, 48-54 (2013).
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).
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).
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).
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).
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).
203. Castagliuolo, I. et al. Neurokinin-1 (NK-1) receptor is required in Clostridium difficile-induced enteritis. J. Clin. Invest. 101, 1547-1550 (1998).
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).