Neuroimmune Interactions in Acute and Chronic Itch

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Neuroimmune Interactions in Pain

Abstract

Itch is a sensory experience of the skin that is familiar to all humans. Recent studies have established that the immune system and central and peripheral nervous systems engage in extensive interactions termed “crosstalk,” which gives rise to both acute and chronic itch pathologies. Peripheral sensory neurons detect itch-triggering stimuli from the environment to transduce pruritic signals. Itch signals travel from nerve fibers in the skin and peripheral nervous system to the spinal cord and brain, eliciting scratch behavior as a response to relieve the irritation caused by itch. The mechanisms underlying itch have also been shown to overlap with molecular circuits involved in pain, suggesting a relationship between the two sensations. We discuss various types of pruritogens, released from immune cells, keratinocytes, neurons, glial cells, and cancer cells, as well as the pruritogen receptors expressed by primary sensory neurons (pruriceptors) and spinal cord neurons. Understanding how neuroimmune interactions modulate acute and chronic itch will be necessary to develop more effective treatments for these pathologies.

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References

  • Aich A, Afrin LB, Gupta K. Mast cell-mediated mechanisms of nociception. Int J Mol Sci. 2015;16(12):29069–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124(4):783–801.

    Article  CAS  PubMed  Google Scholar 

  • Akiyama T, Carstens E. Neural processing of itch. Neuroscience. 2013;250:697–714.

    Article  CAS  PubMed  Google Scholar 

  • Atoyan R, Shander D, Botchkareva NV. Non-neuronal expression of transient receptor potential type A1 (TRPA1) in human skin. J Invest Dermatol. 2009;129(9):2312–5.

    Article  CAS  PubMed  Google Scholar 

  • Aubdool AA, Brain SD. Neurovascular aspects of skin neurogenic inflammation. J Investig Dermatol Symp Proc. 2011;15(1):33–9.

    Article  CAS  PubMed  Google Scholar 

  • Biro T, Toth BI, Marincsak R, Dobrosi N, Geczy T, Paus R. TRP channels as novel players in the pathogenesis and therapy of itch. Biochim Biophys Acta. 2007;1772(8):1004–21.

    Article  CAS  PubMed  Google Scholar 

  • Bogiatzi SI, Fernandez I, Bichet JC, Marloie-Provost MA, Volpe E, Sastre X, Soumelis V. Cutting edge: proinflammatory and Th2 cytokines synergize to induce thymic stromal lymphopoietin production by human skin keratinocytes. J Immunol. 2007;178(6):3373–7.

    Article  CAS  PubMed  Google Scholar 

  • Bork K. Pruritus precipitated by hydroxyethyl starch: a review. Br J Dermatol. 2005;152(1):3–12.

    Article  CAS  PubMed  Google Scholar 

  • Bourane S, Duan B, Koch SC, Dalet A, Britz O, Garcia-Campmany L, Kim E, Cheng L, Ghosh A, Ma Q, Goulding M. Gate control of mechanical itch by a subpopulation of spinal cord interneurons. Science. 2015;350(6260):550–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buddenkotte J, Stroh C, Engels IH, Moormann C, Shpacovitch VM, Seeliger S, Vergnolle N, Vestweber D, Luger TA, Schulze-Osthoff K, et al. Agonists of proteinase-activated receptor-2 stimulate upregulation of intercellular cell adhesion molecule-1 in primary human keratinocytes via activation of NF-kappa B. J Invest Dermatol. 2005;124(1):38–45.

    Article  CAS  PubMed  Google Scholar 

  • Cevikbas F, Lerner EA. Physiology and pathophysiology of itch. Physiol Rev. 2020;100(3):945–82.

    Article  PubMed  Google Scholar 

  • Cevikbas F, Wang X, Akiyama T, Kempkes C, Savinko T, Antal A, Kukova G, Buhl T, Ikoma A, Buddenkotte J, et al. A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: involvement of TRPV1 and TRPA1. J Allergy Clin Immunol. 2014;133(2):448–60.

    Article  CAS  PubMed  Google Scholar 

  • Chan LS, Robinson N, Xu L. Expression of interleukin-4 in the epidermis of transgenic mice results in a pruritic inflammatory skin disease: an experimental animal model to study atopic dermatitis. J Invest Dermatol. 2001;117(4):977–83.

    Article  CAS  PubMed  Google Scholar 

  • Chen O, He Q, Han Q, Furutani K, Gu Y, Olexa M, Ji RR. Mechanisms and treatments of neuropathic itch in a mouse model of lymphoma. J Clin Invest. 2022:e160807. https://doi.org/10.1172/JCI160807.

  • Cornelissen C, Marquardt Y, Czaja K, Wenzel J, Frank J, Luscher-Firzlaff J, Luscher B, Baron JM. IL-31 regulates differentiation and filaggrin expression in human organotypic skin models. J Allergy Clin Immunol. 2012;129(2):426-33, 433.e421–28

    Google Scholar 

  • Cowden JM, Zhang M, Dunford PJ, Thurmond RL. The histamine H4 receptor mediates inflammation and pruritus in Th2-dependent dermal inflammation. J Invest Dermatol. 2010;130(4):1023–33.

    Article  CAS  PubMed  Google Scholar 

  • Cyphert JM, Kovarova M, Allen IC, Hartney JM, Murphy DL, Wess J, Koller BH. Cooperation between mast cells and neurons is essential for antigen-mediated bronchoconstriction. J Immunol. 2009;182(12):7430–9.

    Article  CAS  PubMed  Google Scholar 

  • De Felipe C, Herrero JF, O’Brien JA, Palmer JA, Doyle CA, Smith AJ, Laird JM, Belmonte C, Cervero F, Hunt SP. Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. Nature. 1998;392(6674):394–7.

    Article  PubMed  Google Scholar 

  • Denda M, Tsutsumi M. Roles of transient receptor potential proteins (TRPS) in epidermal keratinocytes. Adv Exp Med Biol. 2011;704:847–60.

    Article  CAS  PubMed  Google Scholar 

  • Dillon SR, Sprecher C, Hammond A, Bilsborough J, Rosenfeld-Franklin M, Presnell SR, Haugen HS, Maurer M, Harder B, Johnston J, et al. Interleukin 31, a cytokine produced by activated t cells, induces dermatitis in mice. Nat Immunol. 2004;5(7):752–60.

    Article  CAS  PubMed  Google Scholar 

  • Dong X, Han S, Zylka MJ, Simon MI, Anderson DJ. A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons. Cell. 2001;106(5):619–32.

    Article  CAS  PubMed  Google Scholar 

  • Du L, Hu X, Yang W, Yasheng H, Liu S, Zhang W, Zhou Y, Cui W, Zhu J, Qiao Z, Maoying Q, Chu Y, Zhou H, Wang Y, Mi W. Spinal IL-33/ST2 signaling mediates chronic itch in mice through the astrocytic JAK2-STAT3 cascade. Glia. 2019;67(9):1680–93.

    PubMed  Google Scholar 

  • Du LX, Zhu JY, Mi WL. Cytokines and chemokines modulation of itch. Neuroscience. 2022;495:74–85.

    Article  CAS  PubMed  Google Scholar 

  • Erickson S, Heul AV, Kim BS. New and emerging treatments for inflammatory itch. Ann Allergy Asthma Immunol. 2021;126(1):13–20.

    Article  CAS  PubMed  Google Scholar 

  • Furutani K, Chen O, McGinnis A, Wang Y, Serhan CN, Hansen TV, Ji RR. Novel pro-resolving lipid mediator mimetic 3-oxa-PD1n-3 DPA reduces acute and chronic itch by modulating excitatory and inhibitory synaptic transmission and astroglial secretion of lipocalin-2 in mice. Pain. 2022; https://doi.org/10.1097/j.pain.0000000000002824.

  • Galli SJ, Nakae S, Tsai M. Mast cells in the development of adaptive immune responses. Nat Immunol. 2005;6(2):135–42.

    Article  CAS  PubMed  Google Scholar 

  • Green DP, Limjunyawong N, Gour N, Pundir P, Dong X. A mast-cell-specific receptor mediates neurogenic inflammation and pain. Neuron. 2019;101(3):412–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Griffiths C, de Bruin-Weller M, Deleuran M, Fargnoli MC, Staumont-Salle D, Hong CH, Sanchez-Carazo J, Foley P, Seo SJ, Msihid J, et al. Dupilumab in adults with moderate-to-severe atopic dermatitis and prior use of systemic non-steroidal immunosuppressants: analysis of four phase 3 trials. Dermatol Ther (Heidelb). 2021;11(4):1357–72.

    Article  PubMed  Google Scholar 

  • Han L, Dong X. Itch mechanisms and circuits. Annu Rev Biophys. 2014;43:331–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han L, Ma C, Liu Q, Weng HJ, Cui Y, Tang Z, Kim Y, Nie H, Qu L, Patel KN, et al. A subpopulation of nociceptors specifically linked to itch. Nat Neurosci. 2013;16(2):174–82.

    Article  CAS  PubMed  Google Scholar 

  • Han Q, Liu D, Convertino M, Wang Z, Jiang C, Kim YH, Luo X, Zhang X, Nackley A, Dokholyan NV, et al. Mirna-711 binds and activates TRPA1 extracellularly to evoke acute and chronic pruritus. Neuron. 2018;99(3):449–63. e446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heise R, Neis MM, Marquardt Y, Joussen S, Heinrich PC, Merk HF, Hermanns HM, Baron JM. IL-31 receptor alpha expression in epidermal keratinocytes is modulated by cell differentiation and interferon gamma. J Invest Dermatol. 2009;129(1):240–3.

    Article  CAS  PubMed  Google Scholar 

  • Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, Horiuchi T, Tomizawa H, Takeda K, Akira S. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol. 2002;3(2):196–200.

    Article  CAS  PubMed  Google Scholar 

  • Ikoma A, Steinhoff M, Stander S, Yosipovitch G, Schmelz M. The neurobiology of itch. Nat Rev Neurosci. 2006;7(7):535–47.

    Article  CAS  PubMed  Google Scholar 

  • Imamachi N, Park GH, Lee H, Anderson DJ, Simon MI, Basbaum AI, Han SK. TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms. Proc Natl Acad Sci U S A. 2009;106:11330–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Indra AK. Epidermal TSLP: a trigger factor for pathogenesis of atopic dermatitis. Expert Rev Proteomics. 2013;10(4):309–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jeong CW, Ahn KS, Rho NK, Park YD, Lee DY, Lee JH, Lee ES, Yang JM. Differential in vivo cytokine mRNA expression in lesional skin of intrinsic vs. extrinsic atopic dermatitis patients using semiquantitative RT-PCR. Clin Exp Allergy. 2003;33(12):1717–24.

    Article  CAS  PubMed  Google Scholar 

  • Ji RR, Donnelly CR, Nedergaard M. Astrocytes in chronic pain and itch. Nat Rev Neurosci. 2019;20:667–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • **g PB, Cao DL, Li SS, Zhu M, Bai XQ, Wu XB, Gao YJ. Chemokine receptor CXCR3 in the spinal cord contributes to chronic itch in mice. Neurosci Bull. 2018;34(1):54–63.

    Article  CAS  PubMed  Google Scholar 

  • Jorizzo JL, Coutts AA, Eady RA, Greaves MW. Vascular responses of human skin to injection of substance p and mechanism of action. Eur J Pharmacol. 1983;87(1):67–76.

    Article  CAS  PubMed  Google Scholar 

  • Kanda N, Watanabe S. Histamine enhances the production of nerve growth factor in human keratinocytes. J Invest Dermatol. 2003;121(3):570–7.

    Article  CAS  PubMed  Google Scholar 

  • Kasraie S, Niebuhr M, Werfel T. Interleukin (IL)-31 activates signal transducer and activator of transcription (STAT)-1, STAT-5 and extracellular signal-regulated kinase 1/2 and down-regulates IL-12p40 production in activated human macrophages. Allergy. 2013;68(6):739–47.

    Article  CAS  PubMed  Google Scholar 

  • Kempkes C, Buddenkotte J, Cevikbas F, Buhl T, Steinhoff M. Role of par-2 in neuroimmune communication and itch. In: Carstens E, Akiyama T, editors. Itch: mechanisms and treatment. Boca Raton: CRC Press; 2014.

    Google Scholar 

  • Kim N, Bae KB, Kim MO, Yu DH, Kim HJ, Yuh HS, Ji YR, Park SJ, Kim S, Son KH, et al. Overexpression of cathepsin s induces chronic atopic dermatitis in mice. J Invest Dermatol. 2012;132(4):1169–76.

    Article  CAS  PubMed  Google Scholar 

  • Koga K, Yamagata R, Kohno K, Yamane T, Shiratori-Hayashi M, Kohro Y, Tozaki-Saitoh H, Tsuda M. Sensitization of spinal itch transmission neurons in a mouse model of chronic itch requires an astrocytic factor. J Allergy Clin Immunol. 2020;145(1):183–191.e10. https://doi.org/10.1016/j.jaci.2019.09.034.

    Article  CAS  PubMed  Google Scholar 

  • Kollmeier A, Francke K, Chen B, Dunford PJ, Greenspan AJ, **a Y, Xu XL, Zhou B, Thurmond RL. The histamine H(4) receptor antagonist, JNJ 39758979, is effective in reducing histamine-induced pruritus in a randomized clinical study in healthy subjects. J Pharmacol Exp Ther. 2014;350(1):181–7.

    Article  PubMed  Google Scholar 

  • Kremer AE, Feramisco J, Reeh PW, Beuers U, Oude Elferink RP. Receptors, cells and circuits involved in pruritus of systemic disorders. Biochim Biophys Acta. 2014;1842(7):869–92.

    Article  CAS  PubMed  Google Scholar 

  • Kroeger KM, Sullivan BM, Locksley RM. IL-18 and iL-33 elicit Th2 cytokines from basophils via a MyD88- and p38alpha-dependent pathway. J Leukoc Biol. 2009;86(4):769–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kubo M. Innate and adaptive type 2 immunity in lung allergic inflammation. Immunol Rev. 2017;278(1):162–72.

    Article  CAS  PubMed  Google Scholar 

  • Kulka M, Sheen CH, Tancowny BP, Grammer LC, Schleimer RP. Neuropeptides activate human mast cell degranulation and chemokine production. Immunology. 2008;123(3):398–410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kwan KY, Glazer JM, Corey DP, Rice FL, Stucky CL. TRPA1 modulates mechanotransduction in cutaneous sensory neurons. J Neurosci. 2009;29(15):4808–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • LaMotte RH, Dong X, Ringkamp M. Sensory neurons and circuits mediating itch. Nat Rev Neurosci. 2014;15(1):19–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leung DY, Boguniewicz M, Howell MD, Nomura I, Hamid QA. New insights into atopic dermatitis. J Clin Invest. 2004;113(5):651–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu T, Ji RR. Oxidative stress induces itch via activation of transient receptor potential subtype ankyrin 1 in mice. Neurosci Bull. 2012;28:145–54.

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu T, Ji RR. New insights into the mechanisms of itch: are pain and itch controlled by distinct mechanisms? Pflugers Arch. 2013;465(12):1671–85.

    Article  CAS  PubMed  Google Scholar 

  • Liu T, Ji RR. Toll-like receptors and itch. In: Carstens E, Akiyama T, editors. Itch: mechanisms and treatment. Boca Raton: CRC Press; 2014.

    Google Scholar 

  • Liu Q, Tang Z, Surdenikova L, Kim S, Patel KN, Kim A, Ru F, Guan Y, Weng HJ, Geng Y, et al. Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell. 2009;139(7):1353–65.

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu T, Xu ZZ, Park CK, Berta T, Ji RR. Toll-like receptor 7 mediates pruritus. Nat Neurosci. 2010;13(12):1460–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu XY, Liu ZC, Sun YG, Ross M, Kim S, Tsai FF, Li QF, Jeffry J, Kim JY, Loh HH, Chen ZF. Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids. Cell. 2011;147(2):447–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu T, Berta T, Xu ZZ, Park CK, Zhang L, Lu N, Liu Q, Liu Y, Gao YJ, Liu YC, et al. TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice. J Clin Invest. 2012;122(6):2195–207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu B, Escalera J, Balakrishna S, Fan L, Caceres AI, Robinson E, Sui A, McKay MC, McAlexander MA, Herrick CA, Jordt SE. TRPA1 controls inflammation and pruritogen responses in allergic contact dermatitis. FASEB J. 2013;27(9):3549–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu T, Han Q, Chen G, Huang Y, Zhao LX, Berta T, Gao YJ, Ji RR. Toll-like receptor 4 contributes to chronic itch, alloknesis, and spinal astrocyte activation in male mice. Pain. 2016;157:806–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luger TA. Neuromediators – a crucial component of the skin immune system. J Dermatol Sci. 2002;30(2):87–93.

    Article  CAS  PubMed  Google Scholar 

  • Ma Q. Labeled lines meet and talk: population coding of somatic sensations. J Clin Invest. 2010;120:3773–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malek M, Gleń J, Rębała K, Kowalczyk A, Sobjanek M, Nowicki R, Ruckemann-Dziurdzińska K, Sokołowska-Wojdyło M. IL-31 does not correlate to pruritus related to early stage cutaneous T-cell lymphomas but is involved in pathogenesis of the disease. Acta Derm Venereol. 2015;95(3):283–8. https://doi.org/10.2340/00015555-1958.

    Article  CAS  PubMed  Google Scholar 

  • McCoy DD, Knowlton WM, McKemy DD. Scra** through the ice: uncovering the role of TRPM8 in cold transduction. Am J Physiol Regul Integr Comp Physiol. 2011;300(6):R1278–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McNeil B, Dong X. Peripheral mechanisms of itch. Neurosci Bull. 2012;28(2):100–10.

    Article  PubMed  PubMed Central  Google Scholar 

  • Melo H, Basso L, Iftinca M, MacNaughton WK, Hollenberg MD, McKay DM, Altier C. Itch induced by peripheral mu opioid receptors is dependent on TRPV1-expressing neurons and alleviated by channel activation. Sci Rep. 2018 Oct 19;8(1):15551. https://doi.org/10.1038/s41598-018-33620-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Metwally SS, Mosaad YM, Abdel-Samee ER, El-Gayyar MA, Abdel-Aziz AM, El-Chennawi FA. IL-13 gene expression in patients with atopic dermatitis: relation to IgE level and to disease severity. Egypt J Immunol. 2004;11(2):171–7.

    PubMed  Google Scholar 

  • Minke B, Cook B. TRP channel proteins and signal transduction. Physiol Rev. 2002;82(2):429–72.

    Article  CAS  PubMed  Google Scholar 

  • Misery L, Brenaut E, Le Garrec R, Abasq C, Genestet S, Marcorelles P, Zagnoli F. Neuropathic pruritus. Nat Rev Neurol. 2014;10(7):408–16.

    Article  PubMed  Google Scholar 

  • Mishra SK, Hoon MA. The cells and circuitry for itch responses in mice. Science. 2013;340(6135):968–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moore C, Gupta R, Jordt SE, Chen Y, Liedtke WB. Regulation of pain and itch by TRP channels. Neurosci Bull. 2018;34:120–42.

    Article  CAS  PubMed  Google Scholar 

  • Moran MM, McAlexander MA, Biro T, Szallasi A. Transient receptor potential channels as therapeutic targets. Nat Rev Drug Discov. 2011;10(8):601–20.

    Article  CAS  PubMed  Google Scholar 

  • Mu D, Deng J, Liu KF, Wu ZY, Shi YF, Guo WM, Mao QQ, Liu XJ, Li H, Sun YG. A central neural circuit for itch sensation. Science. 2017;357(6352):695–9.

    Article  CAS  PubMed  Google Scholar 

  • Nattkemper LA, Zhao ZQ, Nichols AJ, Papoiu ADP, Shively CA, Chen ZF, Yosipovitch G. Overexpression of the gastrin-releasing peptide in cutaneous nerve fibers and its receptor in the spinal cord in primates with chronic itch. J Invest Dermatol. 2013;133(10):2489–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nattkemper LA, Martinez-Escala ME, Gelman AB, Singer EM, Rook AH, Guitart J, Yosipovitch G. Cutaneous T-cell lymphoma and pruritus: the expression of IL-31 and its receptors in the skin. Acta Derm Venereol. 2016;96(7):894–8.

    Article  CAS  PubMed  Google Scholar 

  • Nguyen E, Lim G, Ding H, Hachisuka J, Ko MC, Ross SE. Morphine acts on spinal dynorphin neurons to cause itch through disinhibition. Sci Transl Med. 2021;13(579):eabc3774. https://doi.org/10.1126/scitranslmed.abc3774.

    Article  CAS  PubMed  Google Scholar 

  • Nockher WA, Renz H. Neurotrophins in allergic diseases: from neuronal growth factors to intercellular signaling molecules. J Allergy Clin Immunol. 2006;117(3):583–9.

    Article  CAS  PubMed  Google Scholar 

  • Ochiai S, Jagot F, Kyle RL, Hyde E, White RF, Prout M, Schmidt AJ, Yamane H, Lamiable O, Le Gros G, et al. Thymic stromal lymphopoietin drives the development of IL-13(+) Th2 cells. Proc Natl Acad Sci U S A. 2018;115(5):1033–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oh MH, Oh SY, Lu J, Lou H, Myers AC, Zhu Z, Zheng T. Trpa1-dependent pruritus in IL-13-induced chronic atopic dermatitis. J Immunol. 2013;191(11):5371–82.

    Article  CAS  PubMed  Google Scholar 

  • Ohmatsu H, Sugaya M, Suga H, Morimura S, Miyagaki T, Kai H, Kagami S, Fujita H, Asano Y, Tada Y, et al. Serum IL-31 levels are increased in patients with cutaneous T-cell lymphoma. Acta Derm Venereol. 2012;92(3):282–3.

    Article  CAS  PubMed  Google Scholar 

  • Ohsawa Y, Hirasawa N. The role of histamine H1 and H4 receptors in atopic dermatitis: from basic research to clinical study. Allergol Int. 2014;63(4):533–42.

    Article  CAS  PubMed  Google Scholar 

  • Patel T, Ishiuji Y, Yosipovitch G. Menthol: a refreshing look at this ancient compound. J Am Acad Dermatol. 2007;57(5):873–8.

    Article  PubMed  Google Scholar 

  • Raap U, Wichmann K, Bruder M, Stander S, Wedi B, Kapp A, Werfel T. Correlation of IL-31 serum levels with severity of atopic dermatitis. J Allergy Clin Immunol. 2008;122(2):421–3.

    Article  CAS  PubMed  Google Scholar 

  • Rankin AL, Mumm JB, Murphy E, Turner S, Yu N, McClanahan TK, Bourne PA, Pierce RH, Kastelein R, Pflanz S. IL-33 induces IL-13-dependent cutaneous fibrosis. J Immunol. 2010;184(3):1526–35.

    Article  CAS  PubMed  Google Scholar 

  • Reddy VB, Iuga AO, Shimada SG, LaMotte RH, Lerner EA. Cowhage-evoked itch is mediated by a novel cysteine protease: a ligand of protease-activated receptors. J Neurosci. 2008;28(17):4331–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reddy VB, Shimada SG, Sikand P, Lamotte RH, Lerner EA. Cathepsin S elicits itch and signals via protease-activated receptors. J Invest Dermatol. 2010;130(5):1468–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reich A, Szepietowski JC. Non-analgesic effects of opioids: peripheral opioid receptors as promising targets for future anti-pruritic therapies. Curr Pharm Des. 2012;18:6021–4. https://doi.org/10.2174/138161212803582405.

    Article  CAS  PubMed  Google Scholar 

  • Ringkamp M, Schepers RJ, Shimada SG, Johanek LM, Hartke TV, Borzan J, Shim B, LaMotte RH, Meyer RA. A role for nociceptive, myelinated nerve fibers in itch sensation. J Neurosci. 2011;31(42):14841–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Riol-Blanco L, Ordovas-Montanes J, Perro M, Naval E, Thiriot A, Alvarez D, Paust S, Wood JN, von Andrian UH. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature. 2014;510(7503):157–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ross SE, Mardinly AR, McCord AE, Zurawski J, Cohen S, Jung C, Hu L, Mok SI, Shah A, Savner EM, Tolias C, Corfas R, Chen S, Inquimbert P, Xu Y, McInnes RR, Rice FL, Corfas G, Ma Q, Woolf CJ, Greenberg ME. Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice. Neuron. 2010;65(6):886–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rossbach K, Wendorff S, Sander K, Stark H, Gutzmer R, Werfel T, Kietzmann M, Baumer W. Histamine H4 receptor antagonism reduces hapten-induced scratching behaviour but not inflammation. Exp Dermatol. 2009;18(1):57–63.

    Article  CAS  PubMed  Google Scholar 

  • Sadri N, Schneider RJ. Auf1/Hnrnpd-deficient mice develop pruritic inflammatory skin disease. J Invest Dermatol. 2009;129(3):657–70.

    Article  CAS  PubMed  Google Scholar 

  • Savinko T, Matikainen S, Saarialho-Kere U, Lehto M, Wang G, Lehtimaki S, Karisola P, Reunala T, Wolff H, Lauerma A, et al. IL-33 and ST2 in atopic dermatitis: expression profiles and modulation by triggering factors. J Invest Dermatol. 2012;132(5):1392–400.

    Article  CAS  PubMed  Google Scholar 

  • Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjork HE. Specific C-receptors for itch in human skin. J Neurosci. 1997;17(20):8003–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schmelz M, Schmidt R, Weidner C, Hilliges M, Torebjork HE, Handwerker HO. Chemical response pattern of different classes of c-nociceptors to pruritogens and algogens. J Neurophysiol. 2003;89(5):2441–8.

    Article  CAS  PubMed  Google Scholar 

  • Schwendinger-Schreck J, Wilson SR, Bautista DM. Interactions between keratinocytes and somatosensory neurons in itch. Handb Exp Pharmacol. 2015;226:177–90.

    Article  CAS  PubMed  Google Scholar 

  • Shim WS, Tak MH, Lee MH, Kim M, Kim M, Koo JY, Lee CH, Kim M, Oh U. TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and L2-lipoxygenase. J Neurosci. 2007;27(9):2331–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shiratori-Hayashi M, Tsuda M. Spinal glial cells in itch modulation. Pharmacol Res Perspect. 2021;9(6):e00754. https://doi.org/10.1002/prp2.754.

    Article  PubMed  PubMed Central  Google Scholar 

  • Shiratori-Hayashi M, Koga K, Tozaki-Saitoh H, Kohro Y, Toyonaga H, Yamaguchi C, Hasegawa A, Nakahara T, Hachisuka J, Akira S, Okano H, Furue M, Inoue K, Tsuda M. STAT3-dependent reactive astrogliosis in the spinal dorsal horn underlies chronic itch. Nat Med. 2015;21(8):927–31.

    Article  CAS  PubMed  Google Scholar 

  • Sikand P, Dong X, LaMotte RH. Bam8-22 peptide produces itch and nociceptive sensations in humans independent of histamine release. J Neurosci. 2011;31(20):7563–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Simon D, Braathen LR, Simon HU. Eosinophils and atopic dermatitis. Allergy. 2004;59(6):561–70.

    Article  CAS  PubMed  Google Scholar 

  • Simons FE, Simons KJ. Histamine and H1-antihistamines: celebrating a century of progress. J Allergy Clin Immunol. 2011;128(6):1139–50. e1134

    Article  CAS  PubMed  Google Scholar 

  • Singer EM, Shin DB, Nattkemper LA, Benoit BM, Klein RS, Didigu CA, Loren AW, Dentchev T, Wysocka M, Yosipovitch G, et al. IL-31 is produced by the malignant T-cell population in cutaneous T-cell lymphoma and correlates with CTCL pruritus. J Invest Dermatol. 2013;133(12):2783–5.

    Article  CAS  PubMed  Google Scholar 

  • Soh UJ, Dores MR, Chen B, Trejo J. Signal transduction by protease-activated receptors. Br J Pharmacol. 2010;160(2):191–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sonkoly E, Muller A, Lauerma AI, Pivarcsi A, Soto H, Kemeny L, Alenius H, Dieu-Nosjean MC, Meller S, Rieker J, et al. IL-31: a new link between T cells and pruritus in atopic skin inflammation. J Allergy Clin Immunol. 2006;117(2):411–7.

    Article  CAS  PubMed  Google Scholar 

  • Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, Gilliet M, Ho S, Antonenko S, Lauerma A, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol. 2002;3(7):673–80.

    Article  CAS  PubMed  Google Scholar 

  • Stander S, Moormann C, Schumacher M, Buddenkotte J, Artuc M, Shpacovitch V, Brzoska T, Lippert U, Henz BM, Luger TA, et al. Expression of vanilloid receptor subtype 1 in cutaneous sensory nerve fibers, mast cells, and epithelial cells of appendage structures. Exp Dermatol. 2004;13(3):129–39.

    Article  PubMed  Google Scholar 

  • Steinhoff M, Neisius U, Ikoma A, Fartasch M, Heyer G, Skov PS, Luger TA, Schmelz M. Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin. J Neurosci. 2003a;23(15):6176–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Steinhoff M, Stander S, Seeliger S, Ansel JC, Schmelz M, Luger T. Modern aspects of cutaneous neurogenic inflammation. Arch Dermatol. 2003b;139(11):1479–88.

    Article  PubMed  Google Scholar 

  • Steinhoff M, Bienenstock J, Schmelz M, Maurer M, Wei E, Biro T. Neurophysiological, neuroimmunological, and neuroendocrine basis of pruritus. J Invest Dermatol. 2006;126(8):1705–18.

    Article  CAS  PubMed  Google Scholar 

  • Sun YG, Chen ZF. A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature. 2007;448(7154):700–3.

    Article  CAS  PubMed  Google Scholar 

  • Sun YG, Zhao ZQ, Meng XL, Yin J, Liu XY, Chen ZF. Cellular basis of itch sensation. Science. 2009;325(5947):1531–4.

    Article  CAS  PubMed  Google Scholar 

  • Sun S, Xu Q, Guo C, Guan Y, Liu Q, Dong X. Leaky gate model: intensity-dependent coding of pain and itch in the spinal cord. Neuron. 2017;93(4):840–53.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suzuki A, Suzuki R, Furuno T, Teshima R, Nakanishi M. N-cadherin plays a role in the synapse-like structures between mast cells and neurites. Biol Pharm Bull. 2004;27(12):1891–4.

    Article  CAS  PubMed  Google Scholar 

  • Tay SS, Roediger B, Tong PL, Tikoo S, Weninger W. The skin-resident immune network. Curr Dermatol Rep. 2014;3:13–22.

    Article  PubMed  Google Scholar 

  • Todberg T, Zachariae C, Bregnhøj A, Hedelund L, Bonefeld KK, Nielsen K, Iversen L, Skov L. The effect of botulinum neurotoxin A in patients with plaque psoriasis – an exploratory trial. J Eur Acad Dermatol Venereol. 2018;32(2):e81–2. https://doi.org/10.1111/jdv.14536.

    Article  CAS  PubMed  Google Scholar 

  • Toth BI, Olah A, Szollosi AG, Biro T. TRP channels in the skin. Br J Pharmacol. 2014;171(10):2568–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Valdes-Rodriguez R, Kaushik SB, Yosipovitch G. Transient receptor potential channels and dermatological disorders. Curr Top Med Chem. 2013;13(3):335–43.

    Article  CAS  PubMed  Google Scholar 

  • van der Fits L, Mourits S, Voerman JS, Kant M, Boon L, Laman JD, Cornelissen F, Mus AM, Florencia E, Prens EP, Lubberts E. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol. 2009;182:5836–45.

    Article  PubMed  Google Scholar 

  • van der Kleij HP, Ma D, Redegeld FA, Kraneveld AD, Nijkamp FP, Bienenstock J. Functional expression of neurokinin 1 receptors on mast cells induced by IL-4 and stem cell factor. J Immunol. 2003;171(4):2074–9.

    Article  PubMed  Google Scholar 

  • Verge VM, Richardson PM, Wiesenfeld-Hallin Z, Hokfelt T. Differential influence of nerve growth factor on neuropeptide expression in vivo: a novel role in peptide suppression in adult sensory neurons. J Neurosci. 1995;15(3 Pt 1):2081–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vergnolle N, Ferazzini M, D’Andrea MR, Buddenkotte J, Steinhoff M. Proteinase-activated receptors: novel signals for peripheral nerves. Trends Neurosci. 2003;26(9):496–500.

    Article  CAS  PubMed  Google Scholar 

  • Wang Z, Jiang C, Yao H, Chen O, Rahman S, Gu Y, Zhao J, Huh Y, Ji RR. Central opioid receptors mediate morphine-induced itch and chronic itch via disinhibition. Brain. 2021;144(2):665–81.

    Article  PubMed  Google Scholar 

  • Wilson SR, Gerhold KA, Bifolck-Fisher A, Liu Q, Patel KN, Dong X, Bautista DM. Trpa1 is required for histamine-independent, mas-related g protein-coupled receptor-mediated itch. Nat Neurosci. 2011;14(5):595–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wilson SR, The L, Batia LM, Beattie K, Katibah GE, McClain SP, Pellegrino M, Estandian DM, Bautista DM. The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell. 2013;155(2):285–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xanthos DN, Gaderer S, Drdla R, Nuro E, Abramova A, Ellmeier W, Sandkuhler J. Central nervous system mast cells in peripheral inflammatory nociception. Mol Pain. 2011;7:42.

    Article  PubMed  PubMed Central  Google Scholar 

  • Yamamoto M, Haruna T, Yasui K, Takahashi H, Iduhara M, Takaki S, Deguchi M, Arimura A. A novel atopic dermatitis model induced by topical application with dermatophagoides farinae extract in Nc/Nga mice. Allergol Int. 2007;56(2):139–48.

    Article  PubMed  Google Scholar 

  • Yosipovitch G, Bernhard JD. Clinical practice. Chronic pruritus. N Engl J Med. 2013;368(17):1625–34.

    Article  CAS  PubMed  Google Scholar 

  • Yosipovitch G, Papoiu AD. What causes itch in atopic dermatitis? Curr Allergy Asthma Rep. 2008;8(4):306–11.

    Article  CAS  PubMed  Google Scholar 

  • Zheng T, Oh MH, Oh SY, Schroeder JT, Glick AB, Zhu Z. Transgenic expression of interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling. J Invest Dermatol. 2009;129(3):742–51.

    Article  CAS  PubMed  Google Scholar 

  • Zhuang ZY, Xu H, Clapham DE, Ji RR. Phosphatidylinositol 3-kinase activates ERK in primary sensory neurons and mediates inflammatory heat hyperalgesia through TRPV1 sensitization. J Neurosci. 2004;24(38):8300–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ziegler SF, Roan F, Bell BD, Stoklasek TA, Kitajima M, Han H. The biology of thymic stromal lymphopoietin (TSLP). Adv Pharmacol. 2013;66:129–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zylka MJ, Dong X, Southwell AL, Anderson DJ. Atypical expansion in mice of the sensory neuron-specific Mrg G protein-coupled receptor family. Proc Natl Acad Sci U S A. 2003;100(17):10043–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Chen, O., Rahman, S., Olexa, M., Ji, J., Huh, Y., Ji, RR. (2023). Neuroimmune Interactions in Acute and Chronic Itch. In: Ji, RR., Cheng, J., Ji, J. (eds) Neuroimmune Interactions in Pain . Springer, Cham. https://doi.org/10.1007/978-3-031-29231-6_7

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