Pain and immunity: implications for host defence (original) (raw)

• Scholz, J. & Woolf, C. J. Can we conquer pain? Nat. Neurosci. 5, 1062–1067 (2002).
  CAS PubMed Google Scholar
• Julius, D. & Basbaum, A. I. Molecular mechanisms of nociception. Nature 413, 203–210 (2001).
  CAS PubMed Google Scholar
• Basbaum, A. I., Bautista, D. M., Scherrer, G. & Julius, D. Cellular and molecular mechanisms of pain. Cell 139, 267–284 (2009).
  CAS PubMed PubMed Central Google Scholar
• Chiu, I. M., von Hehn, C. A. & Woolf, C. J. Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nat. Neurosci. 15, 1063–1067 (2012).
  CAS PubMed PubMed Central Google Scholar
• Chiu, I. M., Pinho-Ribeiro, F. A. & Woolf, C. J. Pain and infection: pathogen detection by nociceptors. Pain 157, 1192–1193 (2016).
  PubMed PubMed Central Google Scholar
• Pinho-Ribeiro, F. A., Verri, W. A. Jr & Chiu, I. M. Nociceptor sensory neuron-immune interactions in pain and inflammation. Trends Immunol. 38, 5–19 (2017).
  CAS PubMed Google Scholar
• Baral, P., Mills, K., Pinho-Ribeiro, F. A. & Chiu, I. M. Pain and itch: beneficial or harmful to antimicrobial defense? Cell Host Microbe 19, 755–759 (2016).
  CAS PubMed Google Scholar
• Riol-Blanco, L. et al. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature 510, 157–161 (2014).This study demonstrates the importance of nociceptor-immune interactions in driving DC activation and cutaneous inflammation in a mouse model of psoriasis-like inflammation.
  CAS PubMed PubMed Central Google Scholar
• Kashem, S. W. et al. Nociceptive sensory fibers drive interleukin-23 production from CD301b+ dermal dendritic cells and drive protective cutaneous immunity. Immunity 43, 515–526 (2015).This study shows the protective role of nociceptors in host defence against C. albicans infection in skin by activation of DCs and IL-23 production.
  CAS PubMed PubMed Central Google Scholar
• Engel, M. A. et al. TRPA1 and substance P mediate colitis in mice. Gastroenterology 141, 1346–1358 (2011).This study highlights that the nociceptive ion channel TRPA1 and neuropeptide substance P contribute to the development of inflammation in the gastrointestinal tract in a mouse model of colitis.
  CAS PubMed Google Scholar
• Maruyama, K. et al. Nociceptors boost the resolution of fungal osteoinflammation via the TRP channel-CGRP-Jdp2 Axis. Cell Rep. 19, 2730–2742 (2017).
  CAS PubMed Google Scholar
• Pinho-Ribeiro, F. A. et al. Blocking neuronal signaling to immune cells treats streptococcal invasive infection. Cell 173, 1083–1097 (2018).This study shows that S. pyogenes activates nociceptors through the pore-forming toxin streptolysin S, which causes neural secretion of CGRP and inhibition of neutrophil killing of bacteria.
  CAS PubMed PubMed Central Google Scholar
• Costigan, M., Scholz, J. & Woolf, C. J. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu. Rev. Neurosci. 32, 1–32 (2009).
  CAS PubMed PubMed Central Google Scholar
• Latremoliere, A. & Woolf, C. J. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J. Pain 10, 895–926 (2009).
  PubMed PubMed Central Google Scholar
• 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
• Cook, A. D., Christensen, A. D., Tewari, D., McMahon, S. B. & Hamilton, J. A. Immune cytokines and their receptors in inflammatory pain. Trends Immunol. 39, 240–255 (2018).This recent review comprehensively highlights recent advances in the role of cytokine signalling and receptor expression in pain and raises the question of which cytokine mediators are directly signalling to nociceptors to drive pain.
  CAS PubMed Google Scholar
• White, F. A., Bhangoo, S. K. & Miller, R. J. Chemokines: integrators of pain and inflammation. Nat. Rev. Drug Discov. 4, 834–844 (2005).
  CAS PubMed PubMed Central Google Scholar
• Boettger, M. K. et al. Antinociceptive effects of tumor necrosis factor alpha neutralization in a rat model of antigen-induced arthritis: evidence of a neuronal target. Arthritis Rheum. 58, 2368–2378 (2008).
  CAS PubMed Google Scholar
• Richter, F. et al. Tumor necrosis factor causes persistent sensitization of joint nociceptors to mechanical stimuli in rats. Arthritis Rheum. 62, 3806–3814 (2010).
  CAS PubMed Google Scholar
• Jin, X. & Gereau, R. W. 4th Acute p38-mediated modulation of tetrodotoxin-resistant sodium channels in mouse sensory neurons by tumor necrosis factor-alpha. J. Neurosci. 26, 246–255 (2006).This study demonstrates that TNF-mediated mechanical hypersensitivity involves TNFR1 activity and subsequent p38-dependent modulation of tetrodotoxin-resistant sodium channels in nociceptor neurons.
  CAS PubMed Google Scholar
• Cunha, T. M. et al. A cascade of cytokines mediates mechanical inflammatory hypernociception in mice. Proc. Natl Acad. Sci. USA 102, 1755–1760 (2005).
  CAS PubMed Google Scholar
• Inglis, J. J. et al. Collagen-induced arthritis as a model of hyperalgesia: functional and cellular analysis of the analgesic actions of tumor necrosis factor blockade. Arthritis Rheum. 56, 4015–4023 (2007).
  PubMed Google Scholar
• Zhang, L. et al. TNF-α contributes to spinal cord synaptic plasticity and inflammatory pain: distinct role of TNF receptor subtypes 1 and 2. Pain 152, 419–427 (2011).
  CAS PubMed Google Scholar
• Hess, A. et al. Blockade of TNF-alpha rapidly inhibits pain responses in the central nervous system. Proc. Natl Acad. Sci. USA 108, 3731–3736 (2011).
  CAS PubMed Google Scholar
• Ferreira, S. H., Lorenzetti, B. B., Bristow, A. F. & Poole, S. Interleukin-1β as a potent hyperalgesic agent antagonized by a tripeptide analogue. Nature 334, 698–700 (1988).This is the first definitive study to show the proalgesic role of IL-1β in mice.
  CAS PubMed Google Scholar
• Ebbinghaus, M. et al. The role of interleukin-1β in arthritic pain: main involvement in thermal, but not mechanical, hyperalgesia in rat antigen-induced arthritis. Arthritis Rheum. 64, 3897–3907 (2012).
  CAS PubMed Google Scholar
• Fukuoka, H., Kawatani, M., Hisamitsu, T. & Takeshige, C. Cutaneous hyperalgesia induced by peripheral injection of interleukin-1β in the rat. Brain Res. 657, 133–140 (1994).
  CAS PubMed Google Scholar
• Binshtok, A. M. et al. Nociceptors are interleukin-1β sensors. J. Neurosci. 28, 14062–14073 (2008).
  CAS PubMed PubMed Central Google Scholar
• Thakur, M. et al. Defining the nociceptor transcriptome. Front. Mol. Neurosci. 7, 87 (2014).
  PubMed PubMed Central Google Scholar
• Xu, X. J. et al. Nociceptive responses in interleukin-6-deficient mice to peripheral inflammation and peripheral nerve section. Cytokine 9, 1028–1033 (1997).
  CAS PubMed Google Scholar
• Malsch, P. et al. Deletion of interleukin-6 signal transducer gp130 in small sensory neurons attenuates mechanonociception and down-regulates TRPA1 expression. J. Neurosci. 34, 9845–9856 (2014).
  PubMed PubMed Central Google Scholar
• Vazquez, E. et al. Spinal interleukin-6 is an amplifier of arthritic pain in the rat. Arthritis Rheum. 64, 2233–2242 (2012).
  CAS PubMed Google Scholar
• McNamee, K. E. et al. IL-17 induces hyperalgesia via TNF-dependent neutrophil infiltration. Pain 152, 1838–1845 (2011).
  CAS PubMed Google Scholar
• Pinto, L. G. et al. IL-17 mediates articular hypernociception in antigen-induced arthritis in mice. Pain 148, 247–256 (2010).
  CAS PubMed Google Scholar
• Richter, F. et al. Interleukin-17 sensitizes joint nociceptors to mechanical stimuli and contributes to arthritic pain through neuronal interleukin-17 receptors in rodents. Arthritis Rheum. 64, 4125–4134 (2012).
  CAS PubMed Google Scholar
• Krukowski, K. et al. CD8+ T cells and endogenous IL-10 are required for resolution of chemotherapy-induced neuropathic pain. J. Neurosci. 36, 11074–11083 (2016).
  CAS PubMed PubMed Central Google Scholar
• Milligan, E. D. et al. Controlling pathological pain by adenovirally driven spinal production of the anti-inflammatory cytokine, interleukin-10. Eur. J. Neurosci. 21, 2136–2148 (2005).
  PubMed Google Scholar
• Shen, K. F. et al. Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Exp. Neurol. 247, 466–475 (2013).
  CAS PubMed Google Scholar
• Schweizerhof, M. et al. Hematopoietic colony-stimulating factors mediate tumor-nerve interactions and bone cancer pain. Nat. Med. 15, 802–807 (2009).
  CAS PubMed Google Scholar
• Cook, A. D. et al. Granulocyte-macrophage colony-stimulating factor is a key mediator in inflammatory and arthritic pain. Ann. Rheum. Dis. 72, 265–270 (2013).
  CAS PubMed Google Scholar
• Saleh, R. et al. CSF-1 in inflammatory and arthritic pain development. J. Immunol. 201, 2042–2053 (2018).
  CAS PubMed Google Scholar
• Achuthan, A. et al. Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation. J. Clin. Invest. 126, 3453–3466 (2016).
  PubMed PubMed Central Google Scholar
• Talbot, S., Foster, S. L. & Woolf, C. J. Neuroimmunity: physiology and pathology. Annu. Rev. Immunol. 34, 421–447 (2016).
  CAS PubMed Google Scholar
• Chen, L., Yang, G. & Grosser, T. Prostanoids and inflammatory pain. Prostaglandins Other Lipid Mediat. 104–105, 58–66 (2013).
  PubMed Google Scholar
• Ferreira, S. H. Prostaglandins, aspirin-like drugs and analgesia. Nat. New Biol. 240, 200–203 (1972).
  CAS PubMed Google Scholar
• Samad, T. A. et al. Interleukin-1β-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 410, 471–475 (2001).
  CAS PubMed Google Scholar
• Baba, H., Kohno, T., Moore, K. A. & Woolf, C. J. Direct activation of rat spinal dorsal horn neurons by prostaglandin E2. J. Neurosci. 21, 1750–1756 (2001).
  CAS PubMed Google Scholar
• Levine, J. D., Lau, W., Kwiat, G. & Goetzl, E. J. Leukotriene B4 produces hyperalgesia that is dependent on polymorphonuclear leukocytes. Science 225, 743–745 (1984).This paper demonstrates that LTB 4 directly excites nociceptors to cause hyperalgesia, which is dependent upon leukocytes but is independent of prostaglandin signalling pathways.
  CAS PubMed Google Scholar
• Zinn, S. et al. The leukotriene B4 receptors BLT1 and BLT2 form an antagonistic sensitizing system in peripheral sensory neurons. J. Biol. Chem. 292, 6123–6134 (2017).
  CAS PubMed PubMed Central Google Scholar
• Denk, F., Bennett, D. L. & McMahon, S. B. Nerve growth factor and pain mechanisms. Annu. Rev. Neurosci. 40, 307–325 (2017).
  CAS PubMed Google Scholar
• Mizumura, K. & Murase, S. Role of nerve growth factor in pain. Handb. Exp. Pharmacol. 227, 57–77 (2015).
  CAS PubMed Google Scholar
• Halliday, D. A., Zettler, C., Rush, R. A., Scicchitano, R. & McNeil, J. D. Elevated nerve growth factor levels in the synovial fluid of patients with inflammatory joint disease. Neurochem. Res. 23, 919–922 (1998).
  CAS PubMed Google Scholar
• Lane, N. E. et al. Tanezumab for the treatment of pain from osteoarthritis of the knee. N. Engl. J. Med. 363, 1521–1531 (2010).This human study demonstrates that targeting NGF with a neutralizing antibody, tanezumab, significantly improves pain outcomes in patients with knee osteoarthritis.
  CAS PubMed Google Scholar
• Bannwarth, B. & Kostine, M. Nerve growth factor antagonists: is the future of monoclonal antibodies becoming clearer? Drugs 77, 1377–1387 (2017).
  CAS PubMed Google Scholar
• Ji, R. R., Samad, T. A., Jin, S. X., Schmoll, R. & Woolf, C. J. p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 36, 57–68 (2002).
  CAS PubMed Google Scholar
• Zhang, X., Huang, J. & McNaughton, P. A. NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels. EMBO J. 24, 4211–4223 (2005).
  CAS PubMed PubMed Central Google Scholar
• Kerr, B. J., Souslova, V., McMahon, S. B. & Wood, J. N. A role for the TTX-resistant sodium channel Nav 1.8 in NGF-induced hyperalgesia, but not neuropathic pain. Neuroreport 12, 3077–3080 (2001).
  CAS PubMed Google Scholar
• Coull, J. A. et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438, 1017–1021 (2005).This study demonstrates that signalling from microglia to neurons via BDNF is a crucial contributor to neuropathic pain by driving a shift in the anion gradient.
  CAS PubMed Google Scholar
• Sorge, R. E. et al. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat. Neurosci. 18, 1081–1083 (2015).
  CAS PubMed PubMed Central Google Scholar
• Julius, D. TRP channels and pain. Annu. Rev. Cell Dev. Biol. 29, 355–384 (2013).
  CAS PubMed Google Scholar
• Cheng, J. K. & Ji, R. R. Intracellular signaling in primary sensory neurons and persistent pain. Neurochem. Res. 33, 1970–1978 (2008).
  CAS PubMed PubMed Central Google Scholar
• Chuang, H. H. et al. Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature 411, 957–962 (2001).This study demonstrates that TRPV1, the capsaicin receptor, is sensitized by bradykinin and NGF through their activation of PLC, which mediates PtdIns(4,5)P 2 hydrolysis and release of inhibition of TRPV1 signalling.
  CAS PubMed Google Scholar
• Prescott, E. D. & Julius, D. A modular PIP2 binding site as a determinant of capsaicin receptor sensitivity. Science 300, 1284–1288 (2003).
  CAS PubMed Google Scholar
• Bandell, M. et al. Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 41, 849–857 (2004).
  CAS PubMed Google Scholar
• Premkumar, L. S. & Ahern, G. P. Induction of vanilloid receptor channel activity by protein kinase C. Nature 408, 985–990 (2000).
  CAS PubMed Google Scholar
• Zhang, X., Li, L. & McNaughton, P. A. Proinflammatory mediators modulate the heat-activated ion channel TRPV1 via the scaffolding protein AKAP79/150. Neuron 59, 450–461 (2008).
  PubMed Google Scholar
• Khan, A. A. et al. Tumor necrosis factor alpha enhances the sensitivity of rat trigeminal neurons to capsaicin. Neuroscience 155, 503–509 (2008).
  CAS PubMed Google Scholar
• Fang, D. et al. Interleukin-6-mediated functional upregulation of TRPV1 receptors in dorsal root ganglion neurons through the activation of JAK/PI3K signaling pathway: roles in the development of bone cancer pain in a rat model. Pain 156, 1124–1144 (2015).
  CAS PubMed Google Scholar
• Viana, F. TRPA1 channels: molecular sentinels of cellular stress and tissue damage. J. Physiol. 594, 4151–4169 (2016).
  CAS PubMed PubMed Central Google Scholar
• Obata, K. et al. TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury. J. Clin. Invest. 115, 2393–2401 (2005).
  CAS PubMed PubMed Central Google Scholar
• Schmidt, M., Dubin, A. E., Petrus, M. J., Earley, T. J. & Patapoutian, A. Nociceptive signals induce trafficking of TRPA1 to the plasma membrane. Neuron 64, 498–509 (2009).
  CAS PubMed PubMed Central Google Scholar
• Alessandri-Haber, N. et al. Hypotonicity induces TRPV4-mediated nociception in rat. Neuron 39, 497–511 (2003).
  CAS PubMed Google Scholar
• Alessandri-Haber, N., Dina, O. A., Joseph, E. K., Reichling, D. & Levine, J. D. A transient receptor potential vanilloid 4-dependent mechanism of hyperalgesia is engaged by concerted action of inflammatory mediators. J. Neurosci. 26, 3864–3874 (2006).
  CAS PubMed Google Scholar
• Alessandri-Haber, N. et al. Transient receptor potential vanilloid 4 is essential in chemotherapy-induced neuropathic pain in the rat. J. Neurosci. 24, 4444–4452 (2004).
  CAS PubMed Google Scholar
• Todaka, H., Taniguchi, J., Satoh, J., Mizuno, A. & Suzuki, M. Warm temperature-sensitive transient receptor potential vanilloid 4 (TRPV4) plays an essential role in thermal hyperalgesia. J. Biol. Chem. 279, 35133–35138 (2004).
  CAS PubMed Google Scholar
• Dib-Hajj, S. D., Cummins, T. R., Black, J. A. & Waxman, S. G. Sodium channels in normal and pathological pain. Annu. Rev. Neurosci. 33, 325–347 (2010).
  CAS PubMed Google Scholar
• Black, J. A., Liu, S., Tanaka, M., Cummins, T. R. & Waxman, S. G. Changes in the expression of tetrodotoxin-sensitive sodium channels within dorsal root ganglia neurons in inflammatory pain. Pain 108, 237–247 (2004).
  CAS PubMed Google Scholar
• Strickland, I. T. et al. Changes in the expression of NaV1.7, NaV1.8 and NaV1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain. Eur. J. Pain 12, 564–572 (2008).
  CAS PubMed Google Scholar
• Chiu, I. M. et al. Bacteria activate sensory neurons that modulate pain and inflammation. Nature 501, 52–57 (2013).This study demonstrates activation of nociceptor neurons by the bacterial pathogen S. aureus via the microbial components αHL and N -formyl peptides, which contribute to mechanical and thermal hyperalgesia.
  CAS PubMed PubMed Central Google Scholar
• Blake, K. J. et al. Staphylococcus aureus produces pain through pore-forming toxins and neuronal TRPV1 that is silenced by QX-314. Nat. Commun. 9, 37 (2018).
  PubMed PubMed Central Google Scholar
• Diogenes, A., Ferraz, C. C., Akopian, A. N., Henry, M. A. & Hargreaves, K. M. LPS sensitizes TRPV1 via activation of TLR4 in trigeminal sensory neurons. J. Dent. Res. 90, 759–764 (2011).
  CAS PubMed Google Scholar
• Meseguer, V. et al. TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins. Nat. Commun. 5, 3125 (2014).
  PubMed PubMed Central Google Scholar
• Rudick, C. N. et al. Host-pathogen interactions mediating pain of urinary tract infection. J. Infect. Dis. 201, 1240–1249 (2010).
  CAS PubMed PubMed Central Google Scholar
• Alpizar, Y. A. et al. TRPV4 activation triggers protective responses to bacterial lipopolysaccharides in airway epithelial cells. Nat. Commun. 8, 1059 (2017).
  PubMed PubMed Central Google Scholar
• Xu, Z. Z. et al. Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade. Nat. Med. 21, 1326–1331 (2015).This study demonstrates that TLR5, a TLR that binds to bacterial flagellin, is specifically expressed by a subset of A-fibre neurons that mediate neuropathic pain, which is silenced via delivery of the charged analgesic compound QX-314 with flagellin.
  CAS PubMed PubMed Central Google Scholar
• Yissachar, N. et al. An intestinal organ culture system uncovers a role for the nervous system in microbe-immune crosstalk. Cell 168, 1135–1148 (2017).
  CAS PubMed PubMed Central Google Scholar
• Maruyama, K. et al. The ATP transporter VNUT mediates induction of dectin-1-triggered candida nociception. iScience 6, 306–318 (2018).
  CAS PubMed PubMed Central Google Scholar
• Fields, H. L., Rowbotham, M. & Baron, R. Postherpetic neuralgia: irritable nociceptors and deafferentation. Neurobiol. Dis. 5, 209–227 (1998).
  CAS PubMed Google Scholar
• Steiner, I., Kennedy, P. G. & Pachner, A. R. The neurotropic herpes viruses: herpes simplex and varicella-zoster. Lancet Neurol. 6, 1015–1028 (2007).
  CAS PubMed Google Scholar
• Marion, E. et al. Mycobacterial toxin induces analgesia in buruli ulcer by targeting the angiotensin pathways. Cell 157, 1565–1576 (2014).This paper demonstrates the analgesic action of a M. ulcerans mycolactone via activation of the type II angiotensin signalling pathway in sensory neurons to drive potassium-dependent neuronal hyperpolarization.
  CAS PubMed Google Scholar
• Lotz, M., Vaughan, J. H. & Carson, D. A. Effect of neuropeptides on production of inflammatory cytokines by human monocytes. Science 241, 1218–1221 (1988).
  CAS PubMed Google Scholar
• Sun, J., Ramnath, R. D., Zhi, L., Tamizhselvi, R. & Bhatia, M. Substance P enhances NF-κB transactivation and chemokine response in murine macrophages via ERK1/2 and p38 MAPK signaling pathways. Am. J. Physiol. Cell Physiol. 294, C1586–C1596 (2008).
  CAS PubMed Google Scholar
• Lim, J. E., Chung, E. & Son, Y. A neuropeptide, substance-P, directly induces tissue-repairing M2 like macrophages by activating the PI3K/Akt/mTOR pathway even in the presence of IFNgamma. Sci. Rep. 7, 9417 (2017).
  PubMed PubMed Central Google Scholar
• Hong, H. S. & Son, Y. Substance P ameliorates collagen II-induced arthritis in mice via suppression of the inflammatory response. Biochem. Biophys. Res. Commun. 453, 179–184 (2014).
  CAS PubMed Google Scholar
• Baliu-Pique, M., Jusek, G. & Holzmann, B. Neuroimmunological communication via CGRP promotes the development of a regulatory phenotype in TLR4-stimulated macrophages. Eur. J. Immunol. 44, 3708–3716 (2014).
  CAS PubMed Google Scholar
• 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
• Yaraee, R., Ebtekar, M., Ahmadiani, A. & Sabahi, F. Effect of neuropeptides (SP and CGRP) on antigen presentation by macrophages. Immunopharmacol. Immunotoxicol. 27, 395–404 (2005).
  CAS PubMed Google Scholar
• Russell, F. A., King, R., Smillie, S. J., Kodji, X. & Brain, S. D. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol. Rev. 94, 1099–1142 (2014).
  CAS PubMed PubMed Central Google Scholar
• Harzenetter, M. D. et al. Negative regulation of TLR responses by the neuropeptide CGRP is mediated by the transcriptional repressor ICER. J. Immunol. 179, 607–615 (2007).This study demonstrates that CGRP signals through PKA and ICER to block TLR-dependent induction of TNF and CCL4 in macrophages.
  CAS PubMed Google Scholar
• 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
• 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
• Delgado, M. et al. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit tumor necrosis factor alpha transcriptional activation by regulating nuclear factor-kB and cAMP response element-binding protein/c-Jun. J. Biol. Chem. 273, 31427–31436 (1998).
  CAS PubMed Google Scholar
• Martinez, C. et al. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide modulate endotoxin-induced IL-6 production by murine peritoneal macrophages. J. Leukoc. Biol. 63, 591–601 (1998).
  CAS PubMed Google Scholar
• 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
• Strausbaugh, H. J. et al. Painful stimulation suppresses joint inflammation by inducing shedding of L-selectin from neutrophils. Nat. Med. 5, 1057–1061 (1999).This study shows the importance of nociceptive pathways in limiting joint inflammation by enhancing the shedding of L-selectin from circulating neutrophils, leading to reduced neutrophil recruitment.
  CAS PubMed Google Scholar
• Baral, P. et al. Nociceptor sensory neurons suppress neutrophil and gammadelta T cell responses in bacterial lung infections and lethal pneumonia. Nat. Med. 24, 417–426 (2018).
  CAS PubMed PubMed Central Google Scholar
• Lei, J. et al. Transient receptor potential vanilloid subtype 1 inhibits inflammation and apoptosis via the release of calcitonin gene-related peptide in the heart after myocardial infarction. Cardiology 134, 436–443 (2016).
  CAS PubMed Google Scholar
• Huang, J., Stohl, L. L., Zhou, X., Ding, W. & Granstein, R. D. Calcitonin gene-related peptide inhibits chemokine production by human dermal microvascular endothelial cells. Brain Behav. Immun. 25, 787–799 (2011).
  CAS PubMed PubMed Central Google Scholar
• Zimmerman, B. J., Anderson, D. C. & Granger, D. N. Neuropeptides promote neutrophil adherence to endothelial cell monolayers. Am. J. Physiol. 263, G678–G682 (1992).
  CAS PubMed Google Scholar
• 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
• Mulderry, P. K. et al. Differential expression of alpha-CGRP and beta-CGRP by primary sensory neurons and enteric autonomic neurons of the rat. Neuroscience 25, 195–205 (1988).
  CAS PubMed Google Scholar
• Sui, P. et al. Pulmonary neuroendocrine cells amplify allergic asthma responses. Science 360, eaan8546 (2018).
  PubMed PubMed Central Google Scholar
• Alving, K. et al. Association between histamine-containing mast cells and sensory nerves in the skin and airways of control and capsaicin-treated pigs. Cell Tissue Res. 264, 529–538 (1991).
  CAS PubMed Google Scholar
• Arizono, N. et al. Anatomical variation in mast cell nerve associations in the rat small intestine, heart, lung, and skin. Similarities of distances between neural processes and mast cells, eosinophils, or plasma cells in the jejunal lamina propria. Lab. Invest. 62, 626–634 (1990).
  CAS PubMed Google Scholar
• Stead, R. H. et al. Intestinal mucosal mast cells in normal and nematode-infected rat intestines are in intimate contact with peptidergic nerves. Proc. Natl Acad. Sci. USA 84, 2975–2979 (1987).
  CAS PubMed Google Scholar
• Furuno, T. et al. Cell adhesion molecule 1 (CADM1) on mast cells promotes interaction with dorsal root ganglion neurites by heterophilic binding to nectin-3. J. Neuroimmunol. 250, 50–58 (2012).
  CAS PubMed Google Scholar
• Jarvikallio, A., Harvima, I. T. & Naukkarinen, A. Mast cells, nerves and neuropeptides in atopic dermatitis and nummular eczema. Arch. Dermatol. Res. 295, 2–7 (2003).
  PubMed Google Scholar
• Mollanazar, N. K., Smith, P. K. & Yosipovitch, G. Mediators of chronic pruritus in atopic dermatitis: getting the itch out? Clin. Rev. Allergy Immunol. 51, 263–292 (2016).
  CAS PubMed Google Scholar
• Azimi, E. et al. Dual action of neurokinin-1 antagonists on Mas-related GPCRs. JCI Insight 1, e89362 (2016).
  PubMed PubMed Central Google Scholar
• McNeil, B. D. et al. Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature 519, 237–241 (2015).This study identifies MRGPRB2, the orthologue of human MRGPRX2, as a critical receptor in mast cells that responds to major secretagogues including the nociceptive neuropeptide substance P.
  CAS PubMed Google Scholar
• Bulut, K. et al. Sensory neuropeptides and epithelial cell restitution: the relevance of SP- and CGRP-stimulated mast cells. Int. J. Colorectal Dis. 23, 535–541 (2008).
  PubMed Google Scholar
• Kim, J. H. et al. CGRP, a neurotransmitter of enteric sensory neurons, contributes to the development of food allergy due to the augmentation of microtubule reorganization in mucosal mast cells. Biomed. Res. 35, 285–293 (2014).
  CAS PubMed Google Scholar
• Russo, A. F. CGRP as a neuropeptide in migraine: lessons from mice. Br. J. Clin. Pharmacol. 80, 403–414 (2015).
  PubMed PubMed Central Google Scholar
• Eftekhari, S., Warfvinge, K., Blixt, F. W. & Edvinsson, L. Differentiation of nerve fibers storing CGRP and CGRP receptors in the peripheral trigeminovascular system. J. Pain 14, 1289–1303 (2013).
  CAS PubMed Google Scholar
• Mikami, N. et al. Calcitonin gene-related peptide regulates type IV hypersensitivity through dendritic cell functions. PLOS ONE 9, e86367 (2014).
  PubMed PubMed Central Google Scholar
• 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 PubMed Central Google Scholar
• Delgado, M., Gonzalez-Rey, E. & Ganea, D. VIP/PACAP preferentially attract Th2 effectors through differential regulation of chemokine production by dendritic cells. FASEB J. 18, 1453–1455 (2004).
  CAS PubMed Google Scholar
• Delgado, M., Reduta, A., Sharma, V. & Ganea, D. VIP/PACAP oppositely affects immature and mature dendritic cell expression of CD80/CD86 and the stimulatory activity for CD4+ T cells. J. Leukoc. Biol. 75, 1122–1130 (2004).
  CAS PubMed Google Scholar
• Ding, W. et al. Pituitary adenylate cyclase-activating peptide and vasoactive intestinal polypeptide bias Langerhans cell Ag presentation toward Th17 cells. Eur. J. Immunol. 42, 901–911 (2012).
  CAS PubMed Google Scholar
• de Jong, P. R. et al. TRPM8 on mucosal sensory nerves regulates colitogenic responses by innate immune cells via CGRP. Mucosal Immunol. 8, 491–504 (2015).
  PubMed Google Scholar
• 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
• Wallrapp, A. et al. The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature 549, 351–356 (2017).
  CAS PubMed PubMed Central Google Scholar
• Cardoso, V. et al. Neuronal regulation of type 2 innate lymphoid cells via neuromedin U. Nature 549, 277–281 (2017).
  CAS PubMed PubMed Central Google Scholar
• Nussbaum, J. C. et al. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 502, 245–248 (2013).
  CAS PubMed PubMed Central Google Scholar
• 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
• Ding, W. et al. Calcitonin gene-related peptide-exposed endothelial cells bias antigen presentation to CD4+ T cells toward a Th17 response. J. Immunol. 196, 2181–2194 (2016).
  CAS PubMed PubMed Central Google Scholar
• Talbot, S. et al. Silencing nociceptor neurons reduces allergic airway inflammation. Neuron 87, 341–354 (2015).
  CAS PubMed PubMed Central Google Scholar
• Delgado, M. VIP: a very important peptide in T helper differentiation. Trends Immunol. 24, 221–224 (2003).
  CAS PubMed Google Scholar
• Weinstock, J. V. et al. Substance P regulates Th1-type colitis in IL-10 knockout mice. J. Immunol. 171, 3762–3767 (2003).
  CAS PubMed Google Scholar
• 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
• 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
• Li, W. W. et al. Neuropeptide regulation of adaptive immunity in the tibia fracture model of complex regional pain syndrome. J. Neuroinflamm. 15, 105 (2018).
  Google Scholar
• McGillis, J. P., Humphreys, S., Rangnekar, V. & Ciallella, J. Modulation of B lymphocyte differentiation by calcitonin gene-related peptide (CGRP). I. Characterization of high-affinity CGRP receptors on murine 70Z/3 cells. Cell. Immunol. 150, 391–404 (1993).
  CAS PubMed Google Scholar
• McGillis, J. P., Humphreys, S. & Reid, S. Characterization of functional calcitonin gene-related peptide receptors on rat lymphocytes. J. Immunol. 147, 3482–3489 (1991).
  CAS PubMed Google Scholar
• Payan, D. G., Brewster, D. R., Missirian-Bastian, A. & Goetzl, E. J. Substance P recognition by a subset of human T lymphocytes. J. Clin. Invest. 74, 1532–1539 (1984).
  CAS PubMed PubMed Central Google Scholar
• Reubi, J. C., Horisberger, U., Kappeler, A. & Laissue, J. A. Localization of receptors for vasoactive intestinal peptide, somatostatin, and substance P in distinct compartments of human lymphoid organs. Blood 92, 191–197 (1998).
  CAS PubMed Google Scholar
• Moran, M. M. & Szallasi, A. Targeting nociceptive transient receptor potential channels to treat chronic pain: current state of the field. Br. J. Pharmacol. 175, 2185–2203 (2018).
  CAS PubMed Google Scholar
• Grace, P. M., Hutchinson, M. R., Maier, S. F. & Watkins, L. R. Pathological pain and the neuroimmune interface. Nat. Rev. Immunol. 14, 217–231 (2014).
  CAS PubMed PubMed Central Google Scholar
• Qin, X., Wan, Y. & Wang, X. CCL2 and CXCL1 trigger calcitonin gene-related peptide release by exciting primary nociceptive neurons. J. Neurosci. Res. 82, 51–62 (2005).
  CAS PubMed Google Scholar
• Cao, D. L., Qian, B., Zhang, Z. J., Gao, Y. J. & Wu, X. B. Chemokine receptor CXCR2 in dorsal root ganglion contributes to the maintenance of inflammatory pain. Brain Res. Bull. 127, 219–225 (2016).
  CAS PubMed Google Scholar
• Miller, R. E. et al. CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis. Proc. Natl Acad. Sci. USA 109, 20602–20607 (2012).
  CAS PubMed Google Scholar
• Gao, Y. J. et al. JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J. Neurosci. 29, 4096–4108 (2009).
  CAS PubMed PubMed Central Google Scholar
• Zhang, Z. J., Cao, D. L., Zhang, X., Ji, R. R. & Gao, Y. J. Chemokine contribution to neuropathic pain: respective induction of CXCL1 and CXCR2 in spinal cord astrocytes and neurons. Pain 154, 2185–2197 (2013).
  CAS PubMed PubMed Central Google Scholar
• Jiang, B. C. et al. CXCL13 drives spinal astrocyte activation and neuropathic pain via CXCR5. J. Clin. Invest. 126, 745–761 (2016).
  PubMed PubMed Central Google Scholar
• Biber, K. et al. Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development. EMBO J. 30, 1864–1873 (2011).
  CAS PubMed PubMed Central Google Scholar
• Milligan, E. D. et al. Evidence that exogenous and endogenous fractalkine can induce spinal nociceptive facilitation in rats. Eur. J. Neurosci. 20, 2294–2302 (2004).
  CAS PubMed Google Scholar
• Verge, G. M. et al. Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions. Eur. J. Neurosci. 20, 1150–1160 (2004).
  PubMed Google Scholar