Evolution has yielded multiple complex and complementary mechanisms to detect environmental danger and protect tissues from damage. The nervous system rapidly processes information and coordinates complex defense behaviors, and the immune system eliminates diverse threats by virtue of mobile, specialized cell populations. The two systems are tightly integrated, cooperating in local and systemic reflexes that restore homeostasis in response to tissue injury and infection. They further share a broad common language of cytokines, growth factors, and neuropeptides that enables bidirectional communication. However, this reciprocal cross talk permits amplification of maladaptive feedforward inflammatory loops that contribute to the development of allergy, autoimmunity, itch, and pain. Appreciating the immune and nervous systems as a holistic, coordinated defense system provides both new insights into inflammation and exciting opportunities for managing acute and chronic inflammatory diseases.


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Literature Cited

  1. McMahon SB, Russa FL, Bennett DL. 1.  2015. Crosstalk between the nociceptive and immune systems in host defence and disease. Nat. Rev. Neurosci. 16:389–402 [Google Scholar]
  2. Shepherd AJ, Downing JE, Miyan JA. 2.  2005. Without nerves, immunology remains incomplete—in vivo veritas. Immunology 116:145–63 [Google Scholar]
  3. Chiu IM, Heesters BA, Ghasemlou N, Von Hehn CA, Zhao F. 3.  et al. 2013. Bacteria activate sensory neurons that modulate pain and inflammation. Nature 501:52–57This was the first paper to describe direct neuronal recognition of a pathogen leading to pain. [Google Scholar]
  4. Woolf CJ, Ma Q. 4.  2007. Nociceptors—noxious stimulus detectors. Neuron 55:353–64 [Google Scholar]
  5. Chiu IM, von Hehn CA, Woolf CJ. 5.  2012. Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nat. Neurosci. 15:1063–67 [Google Scholar]
  6. Andersson U, Tracey KJ. 6.  2012. Reflex principles of immunological homeostasis. Annu. Rev. Immunol. 30:313–35 [Google Scholar]
  7. Chovatiya R, Medzhitov R. 7.  2014. Stress, inflammation, and defense of homeostasis. Mol. Cell 54:281–88 [Google Scholar]
  8. Medzhitov R. 8.  2008. Origin and physiological roles of inflammation. Nature 454:428–35 [Google Scholar]
  9. Binshtok AM, Wang H, Zimmermann K, Amaya F, Vardeh D. 9.  et al. 2008. Nociceptors are interleukin-1β sensors. J. Neurosci. 28:14062–73This is an important paper highlighting cytokine-driven C fiber activation in pain. [Google Scholar]
  10. Reddy KC, Andersen EC, Kruglyak L, Kim DH. 10.  2009. A polymorphism in npr-1 is a behavioral determinant of pathogen susceptibility in C. elegans. Science 323:382–84 [Google Scholar]
  11. Talbot S, Abdulnour RE, Burkett PR, Lee S, Cronin SJ. 11.  et al. 2015. Silencing nociceptor neurons reduces allergic airway inflammation. Neuron 87:341–54 [Google Scholar]
  12. von Hehn CA, Baron R, Woolf CJ. 12.  2012. Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron 73:638–52 [Google Scholar]
  13. Bhat R, Steinman L. 13.  2009. Innate and adaptive autoimmunity directed to the central nervous system. Neuron 64:123–32 [Google Scholar]
  14. Ji RR, Xu ZZ, Gao YJ. 14.  2014. Emerging targets in neuroinflammation-driven chronic pain. Nat. Rev. Drug Discov. 13:533–48 [Google Scholar]
  15. Janeway CA Jr, Medzhitov R. 15.  2002. Innate immune recognition. Annu. Rev. Immunol. 20:197–216 [Google Scholar]
  16. Litman GW, Rast JP, Fugmann SD. 16.  2010. The origins of vertebrate adaptive immunity. Nat. Rev. Immunol. 10:543–53 [Google Scholar]
  17. Iwasaki A, Medzhitov R. 17.  2015. Control of adaptive immunity by the innate immune system. Nat. Immunol. 16:343–53 [Google Scholar]
  18. Liu YJ. 18.  2001. Dendritic cell subsets and lineages, and their functions in innate and adaptive immunity. Cell 106:259–62 [Google Scholar]
  19. Metcalfe DD, Baram D, Mekori YA. 19.  1997. Mast cells. Physiol. Rev. 77:1033–79 [Google Scholar]
  20. Barbara G, Wang B, Stanghellini V, de Giorgio R, Cremon C. 20.  et al. 2007. Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome. Gastroenterology 132:26–37 [Google Scholar]
  21. Mayadas TN, Cullere X, Lowell CA. 21.  2014. The multifaceted functions of neutrophils. Annu. Rev. Pathol. 9:181–218 [Google Scholar]
  22. Hume DA. 22.  2015. The many alternative faces of macrophage activation. Front. Immunol. 6:370 [Google Scholar]
  23. Albright TD, Jessell TM, Kandel ER, Posner MI. 23.  2000. Neural science: a century of progress and the mysteries that remain. Cell 100:Suppl.S1–55 [Google Scholar]
  24. Basbaum AI, Bautista DM, Scherrer G, Julius D. 24.  2009. Cellular and molecular mechanisms of pain. Cell 139:267–84 [Google Scholar]
  25. Veres TZ, Shevchenko M, Krasteva G, Spies E, Prenzler F. 25.  et al. 2009. Dendritic cell–nerve clusters are sites of T cell proliferation in allergic airway inflammation. Am. J. Pathol. 174:808–17 [Google Scholar]
  26. Riol-Blanco L, Ordovas-Montanes J, Perro M, Naval E, Thiriot A. 26.  et al. 2014. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature 510:157–61 [Google Scholar]
  27. Franco R, Pacheco R, Lluis C, Ahern GP, O’Connell PJ. 27.  2007. The emergence of neurotransmitters as immune modulators. Trends Immunol. 28:400–7 [Google Scholar]
  28. Ren K, Dubner R. 28.  2010. Interactions between the immune and nervous systems in pain. Nat. Med. 16:1267–76 [Google Scholar]
  29. Voets T, Droogmans G, Wissenbach U, Janssens A, Flockerzi V, Nilius B. 29.  2004. The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels. Nature 430:748–54 [Google Scholar]
  30. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. 30.  1997. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816–24 [Google Scholar]
  31. Zimmermann K, Leffler A, Babes A, Cendan CM, Carr RW. 31.  et al. 2007. Sensory neuron sodium channel Nav1.8 is essential for pain at low temperatures. Nature 447:855–58 [Google Scholar]
  32. Coste B, Mathur J, Schmidt M, Earley TJ, Ranade S. 32.  et al. 2010. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science 330:55–60 [Google Scholar]
  33. Huppa JB, Davis MM. 33.  2003. T-cell-antigen recognition and the immunological synapse. Nat. Rev. Immunol. 3:973–83 [Google Scholar]
  34. Szallasi A, Cortright DN, Blum CA, Eid SR. 34.  2007. The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nat. Rev. Drug Discov. 6:357–72 [Google Scholar]
  35. Waldmann R, Champigny G, Bassilana F, Heurteaux C, Lazdunski M. 35.  1997. A proton-gated cation channel involved in acid-sensing. Nature 386:173–77 [Google Scholar]
  36. Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J. 36.  et al. 2003. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112:819–29 [Google Scholar]
  37. Ikoma A, Steinhoff M, Stander S, Yosipovitch G, Schmelz M. 37.  2006. The neurobiology of itch. Nat. Rev. Neurosci. 7:535–47 [Google Scholar]
  38. McNeil BD, Pundir P, Meeker S, Han L, Undem BJ. 38.  et al. 2015. Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature 519:237–41This novel paper describes mast cell recognition of secretagogues as an essential inducer of pseudo-allergy. [Google Scholar]
  39. Link TM, Park U, Vonakis BM, Raben DM, Soloski MJ, Caterina MJ. 39.  2010. TRPV2 has a pivotal role in macrophage particle binding and phagocytosis. Nat. Immunol. 11:232–39 [Google Scholar]
  40. Bertin S, Aoki-Nonaka Y, de Jong PR, Nohara LL, Xu H. 40.  et al. 2014. The ion channel TRPV1 regulates the activation and proinflammatory properties of CD4+ T cells. Nat. Immunol. 15:1055–63 [Google Scholar]
  41. Akira S, Uematsu S, Takeuchi O. 41.  2006. Pathogen recognition and innate immunity. Cell 124:783–801 [Google Scholar]
  42. Liu T, Gao YJ, Ji RR. 42.  2012. Emerging role of Toll-like receptors in the control of pain and itch. Neurosci. Bull. 28:131–44 [Google Scholar]
  43. Strowig T, Henao-Mejia J, Elinav E, Flavell R. 43.  2012. Inflammasomes in health and disease. Nature 481:278–86 [Google Scholar]
  44. Paul WE, Zhu J. 44.  2010. How are TH2-type immune responses initiated and amplified?. Nat. Rev. Immunol. 10:225–35 [Google Scholar]
  45. Hoogerwerf WA, Zou L, Shenoy M, Sun D, Micci MA. 45.  et al. 2001. The proteinase-activated receptor 2 is involved in nociception. J. Neurosci. 21:9036–42 [Google Scholar]
  46. Liu XJ, Zhang Y, Liu T, Xu ZZ, Park CK. 46.  et al. 2014. Nociceptive neurons regulate innate and adaptive immunity and neuropathic pain through MyD88 adapter. Cell Res. 24:1374–77 [Google Scholar]
  47. Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K. 47.  et al. 2006. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440:228–32 [Google Scholar]
  48. Cook SP, Vulchanova L, Hargreaves KM, Elde R, McCleskey EW. 48.  1997. Distinct ATP receptors on pain-sensing and stretch-sensing neurons. Nature 387:505–8 [Google Scholar]
  49. Sims GP, Rowe DC, Rietdijk ST, Herbst R, Coyle AJ. 49.  2010. HMGB1 and RAGE in inflammation and cancer. Annu. Rev. Immunol. 28:367–88 [Google Scholar]
  50. Agalave NM, Larsson M, Abdelmoaty S, Su J, Baharpoor A. 50.  et al. 2014. Spinal HMGB1 induces TLR4-mediated long-lasting hypersensitivity and glial activation and regulates pain-like behavior in experimental arthritis. Pain 155:1802–13 [Google Scholar]
  51. Augustyniak D, Nowak J, Lundy FT. 51.  2012. Direct and indirect antimicrobial activities of neuropeptides and their therapeutic potential. Curr. Protein Pept. Sci. 13:723–38 [Google Scholar]
  52. Hepburn L, Prajsnar TK, Klapholz C, Moreno P, Loynes CA. 52.  et al. 2014. Innate immunity. A Spaetzle-like role for nerve growth factor β in vertebrate immunity to Staphylococcus aureus. Science 346:641–46This paper shows how a neural factor produced by immune cells has a direct impact on antimicrobial response. [Google Scholar]
  53. Mossner R, Lesch KP. 53.  1998. Role of serotonin in the immune system and in neuroimmune interactions. Brain Behav. Immun. 12:249–71 [Google Scholar]
  54. Wagner R, Myers RR. 54.  1996. Endoneurial injection of TNF-α produces neuropathic pain behaviors. Neuroreport 7:2897–901 [Google Scholar]
  55. Shim WS, Tak MH, Lee MH, Kim M, Kim M. 55.  et al. 2007. TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase. J. Neurosci. 27:2331–37 [Google Scholar]
  56. Samad TA, Sapirstein A, Woolf CJ. 56.  2002. Prostanoids and pain: unraveling mechanisms and revealing therapeutic targets. Trends Mol. Med. 8:390–96 [Google Scholar]
  57. Samad TA, Moore KA, Sapirstein A, Billet S, Allchorne A. 57.  et al. 2001. Interleukin-1β-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 410:471–75 [Google Scholar]
  58. Goswami SC, Mishra SK, Maric D, Kaszas K, Gonnella GL. 58.  et al. 2014. Molecular signatures of mouse TRPV1-lineage neurons revealed by RNA-Seq transcriptome analysis. J. Pain 15:1338–59 [Google Scholar]
  59. Watkins LR, Maier SF, Goehler LE. 59.  1995. Immune activation: the role of pro-inflammatory cytokines in inflammation, illness responses and pathological pain states. Pain 63:289–302 [Google Scholar]
  60. Shu XQ, Mendell LM. 60.  1999. Neurotrophins and hyperalgesia. PNAS 96:7693–96 [Google Scholar]
  61. Zhuang ZY, Xu H, Clapham DE, Ji RR. 61.  2004. Phosphatidylinositol 3-kinase activates ERK in primary sensory neurons and mediates inflammatory heat hyperalgesia through TRPV1 sensitization. J. Neurosci. 24:8300–9 [Google Scholar]
  62. Woolf CJ, Shortland P, Coggeshall RE. 62.  1992. Peripheral nerve injury triggers central sprouting of myelinated afferents. Nature 355:75–78 [Google Scholar]
  63. Julius D. 63.  2013. TRP channels and pain. Annu. Rev. Cell Dev. Biol. 29:355–84 [Google Scholar]
  64. Vardeh D, Wang D, Costigan M, Lazarus M, Saper CB. 64.  et al. 2009. COX2 in CNS neural cells mediates mechanical inflammatory pain hypersensitivity in mice. J. Clin. Investig. 119:287–94 [Google Scholar]
  65. Ji RR, Samad TA, Jin SX, Schmoll R, Woolf CJ. 65.  2002. p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 36:57–68 [Google Scholar]
  66. Hefti FF, Rosenthal A, Walicke PA, Wyatt S, Vergara G. 66.  et al. 2006. Novel class of pain drugs based on antagonism of NGF. Trends Pharmacol. Sci. 27:85–91 [Google Scholar]
  67. Opree A, Kress M. 67.  2000. Involvement of the proinflammatory cytokines tumor necrosis factor-α, IL-1β and IL-6 but not IL-8 in the development of heat hyperalgesia: effects on heat-evoked calcitonin gene-related peptide release from rat skin. J. Neurosci. 20:6289–93 [Google Scholar]
  68. Zhu W, Xu P, Cuascut FX, Hall AK, Oxford GS. 68.  2007. Activin acutely sensitizes dorsal root ganglion neurons and induces hyperalgesia via PKC-mediated potentiation of transient receptor potential vanilloid I. J. Neurosci. 27:13770–80 [Google Scholar]
  69. Jin X, Gereau RW IV. 69.  2006. Acute p38-mediated modulation of tetrodotoxin-resistant sodium channels in mouse sensory neurons by tumor necrosis factor-α. J. Neurosci. 26:246–55 [Google Scholar]
  70. Zhang N, Inan S, Cowan A, Sun R, Wang JM. 70.  et al. 2005. A proinflammatory chemokine, CCL3, sensitizes the heat- and capsaicin-gated ion channel TRPV1. PNAS 102:4536–41 [Google Scholar]
  71. Malin SA, Molliver DC, Koerber HR, Cornuet P, Frye R. 71.  et al. 2006. Glial cell line-derived neurotrophic factor family members sensitize nociceptors in vitro and produce thermal hyperalgesia in vivo. J. Neurosci. 26:8588–99 [Google Scholar]
  72. Bautista DM, Jordt SE, Nikai T, Tsuruda PR, Read AJ. 72.  et al. 2006. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124:1269–82 [Google Scholar]
  73. Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J. 73.  et al. 2000. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288:306–13This was the first paper to describe the TRPV1 knockout phenotype. [Google Scholar]
  74. Davis JB, Gray J, Gunthorpe MJ, Hatcher JP, Davey PT. 74.  et al. 2000. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 405:183–87 [Google Scholar]
  75. Kwan KY, Allchorne AJ, Vollrath MA, Christensen AP, Zhang DS. 75.  et al. 2006. TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction. Neuron 50:277–89 [Google Scholar]
  76. Amaya F, Wang H, Costigan M, Allchorne AJ, Hatcher JP. 76.  et al. 2006. The voltage-gated sodium channel Nav1.9 is an effector of peripheral inflammatory pain hypersensitivity. J. Neurosci. 26:12852–60 [Google Scholar]
  77. Kerr BJ, Souslova V, McMahon SB, Wood JN. 77.  2001. A role for the TTX-resistant sodium channel Nav 1.8 in NGF-induced hyperalgesia, but not neuropathic pain. Neuroreport 12:3077–80 [Google Scholar]
  78. Nassar MA, Stirling LC, Forlani G, Baker MD, Matthews EA. 78.  et al. 2004. Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain. PNAS 101:12706–11 [Google Scholar]
  79. Stirling LC, Forlani G, Baker MD, Wood JN, Matthews EA. 79.  et al. 2005. Nociceptor-specific gene deletion using heterozygous Nav1.8-Cre recombinase mice. Pain 113:27–36 [Google Scholar]
  80. Cevikbas F, Wang X, Akiyama T, Kempkes C, Savinko T. 80.  et al. 2014. A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: involvement of TRPV1 and TRPA1. J. Allergy Clin. Immunol. 133:448–60 [Google Scholar]
  81. Wilson SR, The L, Batia LM, Beattie K, Katibah GE. 81.  et al. 2013. The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell 155:285–95 [Google Scholar]
  82. Mannion RJ, Costigan M, Decosterd I, Amaya F, Ma QP. 82.  et al. 1999. Neurotrophins: peripherally and centrally acting modulators of tactile stimulus-induced inflammatory pain hypersensitivity. PNAS 96:9385–90 [Google Scholar]
  83. Neumann S, Doubell TP, Leslie T, Woolf CJ. 83.  1996. Inflammatory pain hypersensitivity mediated by phenotypic switch in myelinated primary sensory neurons. Nature 384:360–64 [Google Scholar]
  84. Cunin P, Caillon A, Corvaisier M, Garo E, Scotet M. 84.  et al. 2011. 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. 186:4175–82 [Google Scholar]
  85. Barnes PJ. 85.  1996. What is the role of nerves in chronic asthma and symptoms?. Am. J. Respir. Crit. Care Med. 153:S5–8 [Google Scholar]
  86. Hagermark O, Hokfelt T, Pernow B. 86.  1978. Flare and itch induced by substance P in human skin. J. Investig. Dermatol. 71:233–35This is a seminal paper implicating neuropeptides in neurogenic inflammation. [Google Scholar]
  87. Dianzani C, Collino M, Lombardi G, Garbarino G, Fantozzi R. 87.  2003. Substance P increases neutrophil adhesion to human umbilical vein endothelial cells. Br. J. Pharmacol. 139:1103–10 [Google Scholar]
  88. Barnes PJ, Belvisi MG, Rogers DF. 88.  1990. Modulation of neurogenic inflammation: novel approaches to inflammatory disease. Trends Pharmacol. Sci. 11:185–89 [Google Scholar]
  89. Black PH. 89.  2002. Stress and the inflammatory response: a review of neurogenic inflammation. Brain Behav. Immun. 16:622–53 [Google Scholar]
  90. LaMotte RH, Dong X, Ringkamp M. 90.  2014. Sensory neurons and circuits mediating itch. Nat. Rev. Neurosci. 15:19–31 [Google Scholar]
  91. Spiller RC. 91.  2002. Role of nerves in enteric infection. Gut 51:759–62 [Google Scholar]
  92. Ostrowski SM, Belkadi A, Loyd CM, Diaconu D, Ward NL. 92.  2011. Cutaneous denervation of psoriasiform mouse skin improves acanthosis and inflammation in a sensory neuropeptide-dependent manner. J. Investig. Dermatol. 131:1530–38 [Google Scholar]
  93. Jarvikallio A, Harvima IT, Naukkarinen A. 93.  2003. Mast cells, nerves and neuropeptides in atopic dermatitis and nummular eczema. Arch. Dermatol. Res. 295:2–7 [Google Scholar]
  94. Galluzzo M, Talamonti M, Di Stefani A, Chimenti S. 94.  2015. Linear psoriasis following the typical distribution of the sciatic nerve. J. Dermatol. Case Rep. 9:6–11 [Google Scholar]
  95. Beresford L, Orange O, Bell EB, Miyan JA. 95.  2004. Nerve fibres are required to evoke a contact sensitivity response in mice. Immunology 111:118–25This paper provided evidence for neurons impacting recall responses. [Google Scholar]
  96. Coleridge HM, Coleridge JC. 96.  1994. Pulmonary reflexes: neural mechanisms of pulmonary defense. Annu. Rev. Physiol. 56:69–91 [Google Scholar]
  97. Holzer P. 97.  2007. Role of visceral afferent neurons in mucosal inflammation and defense. Curr. Opin. Pharmacol. 7:563–69 [Google Scholar]
  98. Barnes PJ. 98.  1986. Asthma as an axon reflex. Lancet 1:242–45 [Google Scholar]
  99. Davatelis G, Wolpe SD, Sherry B, Dayer JM, Chicheportiche R, Cerami A. 99.  1989. Macrophage inflammatory protein-1: a prostaglandin-independent endogenous pyrogen. Science 243:1066–68 [Google Scholar]
  100. Watkins LR, Goehler LE, Relton JK, Tartaglia N, Silbert L. 100.  et al. 1995. Blockade of interleukin-1 induced hyperthermia by subdiaphragmatic vagotomy: evidence for vagal mediation of immune–brain communication. Neurosci. Lett. 183:27–31 [Google Scholar]
  101. Tracey KJ. 101.  2002. The inflammatory reflex. Nature 420:853–59 [Google Scholar]
  102. Rosas-Ballina M, Olofsson PS, Ochani M, Valdes-Ferrer SI, Levine YA. 102.  et al. 2011. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science 334:98–101 [Google Scholar]
  103. Wang H, Yu M, Ochani M, Amella CA, Tanovic M. 103.  et al. 2003. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature 421:384–88 [Google Scholar]
  104. Riley TP, Neal-McKinney JM, Buelow DR, Konkel ME, Simasko SM. 104.  2013. Capsaicin-sensitive vagal afferent neurons contribute to the detection of pathogenic bacterial colonization in the gut. J. Neuroimmunol. 257:36–45This research delineates the specific subset of sensory neurons that is important in sensing gut pathogens. [Google Scholar]
  105. Brogden KA, Guthmiller JM, Salzet M, Zasloff M. 105.  2005. The nervous system and innate immunity: the neuropeptide connection. Nat. Immunol. 6:558–64 [Google Scholar]
  106. Souza-Moreira L, Campos-Salinas J, Caro M, Gonzalez-Rey E. 106.  2011. Neuropeptides as pleiotropic modulators of the immune response. Neuroendocrinology 94:89–100 [Google Scholar]
  107. Bowden JJ, Baluk P, Lefevre PM, Schoeb TR, Lindsey JR, McDonald DM. 107.  1996. Sensory denervation by neonatal capsaicin treatment exacerbates Mycoplasma pulmonis infection in rat airways. Am. J. Physiol. 270:L393–403 [Google Scholar]
  108. Kashem SW, Riedl MS, Yao C, Honda CN, Vulchanova L, Kaplan DH. 108.  2015. Nociceptive sensory fibers drive interleukin-23 production from CD301b+ dermal dendritic cells and drive protective cutaneous immunity. Immunity 43:3515–26 [Google Scholar]
  109. Fernandes ES, Liang L, Smillie SJ, Kaiser F, Purcell R. 109.  et al. 2012. TRPV1 deletion enhances local inflammation and accelerates the onset of systemic inflammatory response syndrome. J. Immunol. 188:5741–51 [Google Scholar]
  110. Demirbilek S, Ersoy MO, Demirbilek S, Karaman A, Gurbuz N. 110.  et al. 2004. Small-dose capsaicin reduces systemic inflammatory responses in septic rats. Anesthesia Analg. 99:1501–7 [Google Scholar]
  111. Zaki M, Coudron PE, McCuen RW, Harrington L, Chu S, Schubert ML. 111.  2013. H. pylori acutely inhibits gastric secretion by activating CGRP sensory neurons coupled to stimulation of somatostatin and inhibition of histamine secretion. Am. J. Physiol. Gastrointest. Liver Physiol. 304:G715–22 [Google Scholar]
  112. Marion E, Song OR, Christophe T, Babonneau J, Fenistein D. 112.  et al. 2014. Mycobacterial toxin induces analgesia in Buruli ulcer by targeting the angiotensin pathways. Cell 157:1565–76 [Google Scholar]
  113. Sun J, Singh V, Kajino-Sakamoto R, Aballay A. 113.  2011. Neuronal GPCR controls innate immunity by regulating noncanonical unfolded protein response genes. Science 332:729–32 [Google Scholar]
  114. Courtright LJ, Kuzell WC. 114.  1965. Sparing effect of neurological deficit and trauma on the course of adjuvant arthritis in the rat. Ann. Rheum. Dis. 24:360–68This seminal paper indicated that denervation protects from inflammatory arthritis, both clinically and in a rat model. [Google Scholar]
  115. Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K. 115.  2005. Millisecond-timescale, genetically targeted optical control of neural activity. Nat. Neurosci. 8:1263–68 [Google Scholar]
  116. Stangenberg L, Burzyn D, Binstadt BA, Weissleder R, Mahmood U. 116.  et al. 2014. Denervation protects limbs from inflammatory arthritis via an impact on the microvasculature. PNAS 111:11419–24 [Google Scholar]
  117. Levine JD, Clark R, Devor M, Helms C, Moskowitz MA, Basbaum AI. 117.  1984. Intraneuronal substance P contributes to the severity of experimental arthritis. Science 226:547–49This is another seminal paper showing the importance of substance P in inflammatory disease. [Google Scholar]
  118. Kradin R, MacLean J, Duckett S, Schneeberger EE, Waeber C, Pinto C. 118.  1997. Pulmonary response to inhaled antigen: Neuroimmune interactions promote the recruitment of dendritic cells to the lung and the cellular immune response to inhaled antigen. Am. J. Pathol. 150:1735–43 [Google Scholar]
  119. Sanico AM, Atsuta S, Proud D, Togias A. 119.  1997. Dose-dependent effects of capsaicin nasal challenge: in vivo evidence of human airway neurogenic inflammation. J. Allergy Clin. Immunol. 100:632–41 [Google Scholar]
  120. Takami Y, Mantyh CR, Pappas TN, Takahashi T, Koda K, Miyazaki M. 120.  2009. Extrinsic surgical denervation ameliorates TNBS-induced colitis in rats. Hepatogastroenterology 56:682–86 [Google Scholar]
  121. Engel MA, Khalil M, Mueller-Tribbensee SM, Becker C, Neuhuber WL. 121.  et al. 2012. The proximodistal aggravation of colitis depends on substance P released from TRPV1-expressing sensory neurons. J. Gastroenterol. 47:256–65 [Google Scholar]
  122. Gad M, Pedersen AE, Kristensen NN, Fernandez C de F, Claesson MH. 122.  2009. 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. 15:1174–82 [Google Scholar]
  123. Liu S, Hu HZ, Gao N, Gao C, Wang G. 123.  et al. 2003. Neuroimmune interactions in guinea pig stomach and small intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 284:G154–64 [Google Scholar]
  124. Borbely E, Botz B, Bolcskei K, Kenyer T, Kereskai L. 124.  et al. 2015. Capsaicin-sensitive sensory nerves exert complex regulatory functions in the serum-transfer mouse model of autoimmune arthritis. Brain Behav. Immun. 45:50–59 [Google Scholar]
  125. Rosenberg AF, Wolman MA, Franzini-Armstrong C, Granato M. 125.  2012. In vivo nerve–macrophage interactions following peripheral nerve injury. J. Neurosci. 32:3898–909 [Google Scholar]
  126. Marshall JS, Gomi K, Blennerhassett MG, Bienenstock J. 126.  1999. Nerve growth factor modifies the expression of inflammatory cytokines by mast cells via a prostanoid-dependent mechanism. J. Immunol. 162:4271–76 [Google Scholar]
  127. Ahmed AA, Wahbi AH, Nordlin K. 127.  2001. Neuropeptides modulate a murine monocyte/macrophage cell line capacity for phagocytosis and killing of Leishmania major parasites. Immunopharmacol. Immunotoxicol. 23:397–409 [Google Scholar]
  128. Kincy-Cain T, Bost KL. 128.  1997. Substance P-induced IL-12 production by murine macrophages. J. Immunol. 158:2334–39 [Google Scholar]
  129. Mathers AR, Tckacheva OA, Janelsins BM, Shufesky WJ, Morelli AE, Larregina AT. 129.  2007. In vivo signaling through the neurokinin 1 receptor favors transgene expression by Langerhans cells and promotes the generation of Th1- and Tc1-biased immune responses. J. Immunol. 178:7006–17 [Google Scholar]
  130. Ding W, Stohl LL, Wagner JA, Granstein RD. 130.  2008. Calcitonin gene-related peptide biases Langerhans cells toward Th2-type immunity. J. Immunol. 181:6020–26 [Google Scholar]
  131. Rochlitzer S, Veres TZ, Kuhne K, Prenzler F, Pilzner C. 131.  et al. 2011. The neuropeptide calcitonin gene-related peptide affects allergic airway inflammation by modulating dendritic cell function. Clin. Exp. Allergy 41:1609–21 [Google Scholar]
  132. Jimeno R, Leceta J, Martinez C, Gutierrez-Canas I, Perez-Garcia S. 132.  et al. 2012. Effect of VIP on the balance between cytokines and master regulators of activated helper T cells. Immunol. Cell Biol. 90:178–86 [Google Scholar]
  133. Ganea D, Delgado M. 133.  2001. Neuropeptides as modulators of macrophage functions. Regulation of cytokine production and antigen presentation by VIP and PACAP. Arch. Immunol. Ther. Exp. 49:101–10 [Google Scholar]
  134. Delgado M, Ganea D. 134.  2013. Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune functions. Amino Acids 45:25–39 [Google Scholar]
  135. Nussbaum JC, Van Dyken SJ, von Moltke J, Cheng LE, Mohapatra A. 135.  et al. 2013. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 502:245–48 [Google Scholar]
  136. Hosoi J, Murphy GF, Egan CL, Lerner EA, Grabbe S. 136.  et al. 1993. Regulation of Langerhans cell function by nerves containing calcitonin gene-related peptide. Nature 363:159–63 [Google Scholar]
  137. de Jong PR, Takahashi N, Peiris M, Bertin S, Lee J. 137.  et al. 2015. TRPM8 on mucosal sensory nerves regulates colitogenic responses by innate immune cells via CGRP. Mucosal Immunol. 8:491–504 [Google Scholar]
  138. Canning BJ, Spina D. 138.  2009. Sensory nerves and airway irritability. Handb. Exp. Pharmacol. 194:139–83 [Google Scholar]
  139. Patterson RN, Johnston BT, Ardill JE, Heaney LG, McGarvey LP. 139.  2007. Increased tachykinin levels in induced sputum from asthmatic and cough patients with acid reflux. Thorax 62:491–95 [Google Scholar]
  140. Gu Q, Wiggers ME, Gleich GJ, Lee LY. 140.  2008. Sensitization of isolated rat vagal pulmonary sensory neurons by eosinophil-derived cationic proteins. Am. J. Physiol. Lung Cell. Mol. Physiol. 294:L544–52 [Google Scholar]
  141. Lieu TM, Myers AC, Meeker S, Undem BJ. 141.  2012. TRPV1 induction in airway vagal low-threshold mechanosensory neurons by allergen challenge and neurotrophic factors. Am. J. Physiol. Lung Cell. Mol. Physiol. 302:L941–48 [Google Scholar]
  142. Undem BJ, Taylor-Clark T. 142.  2014. Mechanisms underlying the neuronal-based symptoms of allergy. J. Allergy Clin. Immunol. 133:1521–34 [Google Scholar]
  143. Bonini S, Lambiase A, Bonini S, Angelucci F, Magrini L. 143.  et al. 1996. Circulating nerve growth factor levels are increased in humans with allergic diseases and asthma. PNAS 93:10955–60 [Google Scholar]
  144. Sanico AM, Stanisz AM, Gleeson TD, Bora S, Proud D. 144.  et al. 2000. Nerve growth factor expression and release in allergic inflammatory disease of the upper airways. Am. J. Respir. Crit. Care Med. 161:1631–35 [Google Scholar]
  145. Raychaudhuri SP, Jiang WY, Farber EM. 145.  1998. Psoriatic keratinocytes express high levels of nerve growth factor. Acta Derm. Venereol. 78:84–86 [Google Scholar]
  146. Kakurai M, Monteforte R, Suto H, Tsai M, Nakae S, Galli SJ. 146.  2006. Mast cell-derived tumor necrosis factor can promote nerve fiber elongation in the skin during contact hypersensitivity in mice. Am. J. Pathol. 169:1713–21 [Google Scholar]
  147. Iyer SM, Montgomery KL, Towne C, Lee SY, Ramakrishnan C. 147.  et al. 2014. Virally mediated optogenetic excitation and inhibition of pain in freely moving nontransgenic mice. Nat. Biotechnol. 32:274–78 [Google Scholar]
  148. Armbruster BN, Li X, Pausch MH, Herlitze S, Roth BL. 148.  2007. Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. PNAS 104:5163–68 [Google Scholar]
  149. Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. 149.  2012. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337:816–21 [Google Scholar]
  150. Wainger BJ, Buttermore ED, Oliveira JT, Mellin C, Lee S. 150.  et al. 2015. Modeling pain in vitro using nociceptor neurons reprogrammed from fibroblasts. Nat. Neurosci. 18:17–24 [Google Scholar]

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