Interactions Between Keratinocytes and Somatosensory Neurons in Itch

Part of the Handbook of Experimental Pharmacology book series (HEP, volume 226)


Keratinocytes are epithelial cells that make up the stratified epidermis of the skin. Recent studies suggest that keratinocytes promote chronic itch. Changes in skin morphology that accompany a variety of chronic itch disorders and the multitude of inflammatory mediators secreted by keratinocytes that target both sensory neurons and immune cells highlight the importance of investigating the connection between keratinocytes and chronic itch. This chapter addresses some of the most recent data and models for the role keratinocytes play in the development and maintenance of chronic itch.


Atopic dermatitis Chronic itch Cytokines DRG Keratinocytes Neurogenic inflammation TSLP 



Atopic dermatitis


Calcitonin receptor-like receptor


Chemokine ligand 5


Calcitonin gene-related peptide


Dorsal root ganglia


Endoplasmic reticulum




Histamine 1 receptor






Nuclear factor of activated T cells


Nerve growth factor


Neurokinin 1 receptor


Calcium release-activated calcium channel protein 1


Protease-activated receptor 2




Substance P


T helper type 2


Transient receptor potential cation channel A1


Transient receptor potential cation channel V1


Thymic stromal lymphopoietin


Vascular cellular adhesion molecule 1


  1. Ansel JC, Armstrong CA, Song I, Quinlan KL, Olerud JE, Caughman SW, Bunnett NW (1997) Interactions of the skin and nervous system. J Investig Dermatol Symp Proc 2(1):23–26PubMedCrossRefGoogle Scholar
  2. Bautista DM, Wilson SR, Hoon MA (2014) Why we scratch an itch: the molecules, cells and circuits of itch. Nat Neurosci 17(2):175–182PubMedCentralPubMedCrossRefGoogle Scholar
  3. Boguniewicz M, Leung DYM (2011) Atopic dermatitis: a disease of altered skin barrier and immune dysregulation. Immunol Rev 242(1):233–246PubMedCentralPubMedCrossRefGoogle Scholar
  4. Briot A, Deraison C, Lacroix M, Bonnart C, Robin A, Besson C, Dubus P, Hovnanian A (2009) Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. J Exp Med 206(5):1135–1147PubMedCentralPubMedCrossRefGoogle Scholar
  5. Cevikbas F, Wang X, Akiyama T, Kempkes C, Savinko T, Antal A, Kukova G, Buhl T (2014) A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: involvement of TRPV1 and TRPA1. J Allergy Clin Immunol 133(2):448–460Google Scholar
  6. Chatterjea D, Martinov T (2014) Mast cells: versatile gatekeepers of pain. Mol Immunol: 63(1):38–44Google Scholar
  7. Dallos A, Kiss M, Polyánka H, Dobozy A, Kemeny L, Husz S (2006) Effects of the neuropeptides substance P, calcitonin gene-related peptide, vasoactive intestinal polypeptide and galanin on the production of nerve growth factor and inflammatory cytokines in cultured human keratinocytes. Neuropeptides 40(4):251–263PubMedCrossRefGoogle Scholar
  8. Di Marco E, Marchisio PC, Bondanza S, Franzi AT, Cancedda R, De Luca M (1991) Growth-regulated synthesis and secretion of biologically active nerve growth factor by human keratinocytes. J Biol Chem 266(32):21718–21722PubMedGoogle Scholar
  9. Dong X, Han S, Zylka MJ, Simon MI, Anderson DJ (2001) A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons. Cell 106(5):619–632PubMedCrossRefGoogle Scholar
  10. Elias PM, Schmuth M (2009) Abnormal skin barrier in the etiopathogenesis of atopic dermatitis. Curr Allergy Asthma Rep 9(4):265–272PubMedCrossRefGoogle Scholar
  11. Elmariah SB, Lerner EA (2011) Topical therapies for pruritus. Semin Cutan Med Surg 30(2):118–126PubMedCentralPubMedCrossRefGoogle Scholar
  12. Elmariah SB, Reddy VB, Lerner EA (2014) Cathepsin S signals via PAR2 and generates a novel tethered ligand receptor agonist. PLoS One 9(6):e99702PubMedCentralPubMedCrossRefGoogle Scholar
  13. Furio L, de Veer S, Jaillet M, Briot A, Robin A, Deraison C, Hovnanian A (2014) Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome. J Exp Med 211(3):499–513PubMedCentralPubMedCrossRefGoogle Scholar
  14. Gao P-S, Rafaels NM, Mu D, Hand T, Murray T, Boguniewicz M, Hata T, Schneider L, Hanifin JM, Gallo RL, Gao L, Beaty TH, Beck LA, Leung DYM, Barnes KC (2010) Genetic variants in thymic stromal lymphopoietin are associated with atopic dermatitis and eczema herpeticum. J Allergy Clin Immunol 125(6):1403–1407Google Scholar
  15. Girardi M (2006) Immunosurveillance and immunoregulation by γδ T cells. J Investig Dermatol 126(1):25–31PubMedCrossRefGoogle Scholar
  16. Giustizieri ML, Albanesi C, Fluhr J, Gisondi P, Norgauer J, Girolomoni G (2004) H1 histamine receptor mediates inflammatory responses in human keratinocytes. J Allergy Clin Immunol 114(5):1176–1182PubMedCrossRefGoogle Scholar
  17. Gomes LO, Hara DB, Rae GA (2012) Endothelin-1 induces itch and pain in the mouse cheek model. Life Sci 91(13–14):628–633PubMedCrossRefGoogle Scholar
  18. Gutowska-Owsiak D, Ogg GS (2012) Cytokine regulation of the epidermal barrier. Clin Exp Allergy: 43(6):586–598Google Scholar
  19. Han L, Ma C, Liu Q, Weng HJ, Cui Y, Tang Z, Kim Y, Nie H, Qu L, Patel KN, Li Z, McNeil B, He S, Guan Y, Xiao B, Lamotte RH, Dong X (2013) A subpopulation of nociceptors specifically linked to itch. Nat Neurosci 16(2):174–182PubMedCentralPubMedCrossRefGoogle Scholar
  20. Hatano Y, Man M-Q, Uchida Y, Crumrine D, Scharschmidt TC, Kim EG, Mauro TM, Feingold KR, Elias PM, Holleran WM (2009) Maintenance of an acidic stratum corneum prevents emergence of murine atopic dermatitis. J Invest Dermatol 129(7):1824–1835PubMedCentralPubMedCrossRefGoogle Scholar
  21. Hilliges M, Wang L, Johansson O (1995) Ultrastructural evidence for nerve fibers within all vital layers of the human epidermis. J Investig Dermatol 104(1):134–137Google Scholar
  22. Hirano R, Hasegawa S, Hashimoto K, Haneda Y, Ohsaki A, Ichiyama T (2011) Human thymic stromal lymphopoietin enhances expression of CD80 in human CD14+ monocytes/macrophages. Inflamm Res 60(6):605–610PubMedCrossRefGoogle Scholar
  23. Ikoma A, Steinhoff M, Stander S, Yosipovitch G, Schmelz M (2006) The neurobiology of itch. Nat Rev Neurosci 7(7):535–547PubMedCrossRefGoogle Scholar
  24. Imamachi N, Park GH, Lee H, Anderson DJ, Simon MI, Basbaum AI, Han SK (2009) TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms. Proc Natl Acad Sci USA 106(27):11330–11335PubMedCentralPubMedCrossRefGoogle Scholar
  25. Inami Y, Andoh T, Sasaki A, Kuraishi Y (2013) Topical surfactant-induced pruritus: involvement of histamine released from epidermal keratinocytes. J Pharmacol Exp Ther 344(2):459–466PubMedCrossRefGoogle Scholar
  26. Jeffry J, Kim S, Chen ZF (2011) Itch signaling in the nervous system. Physiology (Bethesda) 26(4):286–292CrossRefGoogle Scholar
  27. Johansson O, Liang Y, Emtestam L (2002) Increased nerve growth factor- and tyrosine kinase A-like immunoreactivities in prurigo nodularis skin—an exploration of the cause of neurohyperplasia. Arch Dermatol Res 293(12):614–619PubMedCrossRefGoogle Scholar
  28. Kabashima K (2013) New concept of the pathogenesis of atopic dermatitis: interplay among the barrier, allergy, and pruritus as a trinity. J Dermatol Sci 70(1):3–11PubMedCrossRefGoogle Scholar
  29. Khodorova A, Navarro B, Jouaville LS, Murphy JE, Rice FL, Mazurkiewicz JE, Long-Woodward D, Stoffel M, Strichartz GR, Yukhananov R, Davar G (2003) Endothelin-B receptor activation triggers an endogenous analgesic cascade at sites of peripheral injury. Nat Med 9(8):1055–1061PubMedCrossRefGoogle Scholar
  30. Kido-Nakahara M, Buddenkotte J, Kempkes C, Ikoma A, Cevikbas F, Akiyama T, Nunes F, Seeliger S, Hasdemir B, Mess C, Buhl T, Sulk M, Müller F-U, Metze D, Bunnett NW, Bhargava A, Carstens E, Furue M, Steinhoff M (2014) Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1–induced pruritus. J Clin Invest 124(6):2683–95PubMedCentralPubMedCrossRefGoogle Scholar
  31. Kim BM, Lee SH, Shim WS, Oh U (2004) Histamine-induced Ca(2+) influx via the PLA(2)/lipoxygenase/TRPV1 pathway in rat sensory neurons. Neurosci Lett 361(1–3):159–162PubMedCrossRefGoogle Scholar
  32. Kim N, Bae KB, Kim MO, Yu DH, Kim HJ, Yuh HS, Ji YR, Park SJ, Kim S, Son K-H, Park S-J, Yoon D, Lee D-S, Lee S, Lee H-S, Kim T-Y, Ryoo ZY (2011) Overexpression of cathepsin S induces chronic atopic dermatitis in mice. J Investig Dermatol 132(4):1169–1176PubMedCrossRefGoogle Scholar
  33. Kim BS, Siracusa MC, Saenz SA, Noti M, Monticelli LA, Sonnenberg GF, Hepworth MR, Van Voorhees AS, Comeau MR, Artis D (2013) TSLP Elicits IL-33-Independent Innate Lymphoid Cell Responses to Promote Skin Inflammation. Sci Transl Med 5(170):170ra16PubMedCentralPubMedCrossRefGoogle Scholar
  34. Kohda F, Koga T, Uchi H, Urabe K, Furue M (2002) Histamine-induced IL-6 and IL-8 production are differentially modulated by IFN-gamma and IL-4 in human keratinocytes. J Dermatol Sci 28(1):34–41PubMedCrossRefGoogle Scholar
  35. Komatsu N, Saijoh K, Kuk C, Liu AC, Khan S, Shirasaki F, Takehara K, Diamandis EP (2007) Human tissue kallikrein expression in the stratum corneum and serum of atopic dermatitis patients. Exp Dermatol 16(6):513–519PubMedCrossRefGoogle Scholar
  36. Leung DY (2013) New insights into atopic dermatitis: role of skin barrier and immune dysregulation. Allergol Int 62(2):151–161PubMedCrossRefGoogle Scholar
  37. Li M, Messaddeq N, Teletin M, Pasquali J-L, Metzger D, Chambon P (2005) Retinoid X receptor ablation in adult mouse keratinocytes generates an atopic dermatitis triggered by thymic stromal lymphopoietin. Proc Natl Acad Sci USA 102(41):14795–14800PubMedCentralPubMedCrossRefGoogle Scholar
  38. Liang J, Kawamata T, Ji W (2010) Molecular signaling of pruritus induced by endothelin-1 in mice. Exp Biol Med 235(11):1300–1305CrossRefGoogle Scholar
  39. Liu Q, Tang Z, Surdenikova L, Kim S, Patel KN, Kim A, Ru F, Guan Y, Weng HJ, Geng Y, Undem BJ, Kollarik M, Chen ZF, Anderson DJ, Dong X (2009) Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell 139(7):1353–1365PubMedCentralPubMedCrossRefGoogle Scholar
  40. Lumpkin EA, Caterina MJ (2007) Mechanisms of sensory transduction in the skin. Nature 445(7130):858–865PubMedCrossRefGoogle Scholar
  41. Malaviya R, Morrison AR, Pentland AP (1996) Histamine in human epidermal cells is induced by ultraviolet light injury. J Invest Dermatol 106(4):785–789PubMedCrossRefGoogle Scholar
  42. McCoy ES, Taylor-Blake B, Street SE, Pribisko AL, Zheng J, Zylka MJ (2013) Peptidergic CGRPalpha primary sensory neurons encode heat and itch and tonically suppress sensitivity to cold. Neuron 78(1):138–151PubMedCentralPubMedCrossRefGoogle Scholar
  43. Neis M, Peters B, Dreuw A, Wenzel J, Bieber T, Mauch C, Krieg T, Stanzel S, Heinrich P, Merk H (2006) Enhanced expression levels of IL-31 correlate with IL-4 and IL-13 in atopic and allergic contact dermatitis. J Allergy Clin Immunol 118(4):930–937PubMedCrossRefGoogle Scholar
  44. Patel T, Yosipovitch G (2010a) The management of chronic pruritus in the elderly. Skin Therapy Lett 15(8):5–9PubMedGoogle Scholar
  45. Patel T, Yosipovitch G (2010b) Therapy of pruritus. Expert Opin Pharmacother 11(10):1673–1682PubMedCentralPubMedCrossRefGoogle Scholar
  46. Raap U, Stander S, Metz M (2011) Pathophysiology of itch and new treatments. Curr Opin Allergy Clin Immunol 11(5):420–427PubMedCrossRefGoogle Scholar
  47. Raychaudhuri SP, Raychaudhuri SK (2004) Role of NGF and neurogenic inflammation in the pathogenesis of psoriasis. Prog Brain Res 146:433–437PubMedCrossRefGoogle Scholar
  48. Reddy VB, Shimada SG, Sikand P, Lamotte RH, Lerner EA (2010) Cathepsin S elicits itch and signals via protease-activated receptors. J Investig Dermatol 130(5):1468–1470PubMedCentralPubMedCrossRefGoogle Scholar
  49. Richardson JD, Vasko MR (2002) Cellular mechanisms of neurogenic inflammation. J Pharmacol Exp Ther 302(3):839–845PubMedCrossRefGoogle Scholar
  50. Roggenkamp D, Kopnick S, Stab F, Wenck H, Schmelz M, Neufang G (2013) Epidermal nerve fibers modulate keratinocyte growth via neuropeptide signaling in an innervated skin model. J Invest Dermatol 133(6):1620–1628PubMedCrossRefGoogle Scholar
  51. Santulli RJ, Derian CK, Darrow AL, Tomko KA, Eckardt AJ, Seiberg M, Scarborough RM, Andrade-Gordon P (1995) Evidence for the presence of a protease-activated receptor distinct from the thrombin receptor in human keratinocytes. Proc Natl Acad Sci USA 92(20):9151–9155PubMedCentralPubMedCrossRefGoogle Scholar
  52. Simpson CL, Patel DM, Green KJ (2011) Deconstructing the skin: cytoarchitectural determinants of epidermal morphogenesis. Nat Rev Mol Cell Biol 12(9):565–580PubMedCentralPubMedCrossRefGoogle Scholar
  53. Siniewicz-Luzeńczyk K, Stańczyk-Przyłuska A, Zeman K (2013) Correlation between serum interleukin 31 level and the severity of disease in children with atopic dermatitis. Adv Dermatol Allergol 5:282–285CrossRefGoogle Scholar
  54. Siracusa MC, Saenz SA, Hill DA, Kim BS, Headley MB, Doering TA, Wherry EJ, Jessup HK, Siegel LA, Kambayashi T, Dudek EC, Kubo M, Cianferoni A, Spergel JM, Ziegler SF, Comeau MR, Artis D (2011) TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation. Nature 477(7363):229–233PubMedCentralPubMedCrossRefGoogle Scholar
  55. Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, Gilliet M, Ho S, Antonenko S, Lauerma A, Smith K, Gorman D, Zurawski S, Abrams J, Menon S, McClanahan T, de Waal-Malefyt R, Bazan F, Kastelein RA, Liu Y-J (2002) Human epithelial cells trigger dendritic cell-mediated allergic inflammation by producing TSLP. Nat Immunol 3(7):673–680PubMedGoogle Scholar
  56. Stefansson K, Brattsand M, Roosterman D, Kempkes C, Bocheva G, Steinhoff M, Egelrud T (2008) Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases. J Invest Dermatol 128(1):18–25PubMedCrossRefGoogle Scholar
  57. Steinhoff M, Neisius U, Ikoma A, Fartasch M, Heyer G, Skov PS, Luger TA, Schmelz M (2003) Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin. J Neurosci 23(15):6176–6180PubMedGoogle Scholar
  58. Tanaka RJ, Ono M, Harrington HA (2011) Skin barrier homeostasis in atopic dermatitis: feedback regulation of kallikrein activity. PLoS One 6(5):e19895PubMedCentralPubMedCrossRefGoogle Scholar
  59. Tay SS, Roediger B, Tong PL, Tikoo S, Weninger W (2013) The skin-resident immune network. Curr Dermatol Rep 3(1):13–22PubMedCentralPubMedCrossRefGoogle Scholar
  60. Toyoda M, Nakamura M, Makino T, Hino T, Kagoura M, Morohashi M (2002) Nerve growth factor and substance P are useful plasma markers of disease activity in atopic dermatitis. Br J Dermatol 147(1):71–79PubMedCrossRefGoogle Scholar
  61. Urashima R, Mihara M (1998) Cutaneous nerves in atopic dermatitis. Virchows Arch 432(4):363–370PubMedCrossRefGoogle Scholar
  62. Viodé C, Lejeune O, Turlier V, Rouquier A, Casas C, Mengeaud V, Redoulès D, Schmitt A-M (2014) Cathepsin S, a new pruritus biomarker in clinical dandruff/seborrhoeic dermatitis evaluation. Exp Dermatol 23(4):274–275PubMedCrossRefGoogle Scholar
  63. Willis WD Jr, Coggeshall RE (1991) Sensory mechanisms of the spinal cord, 2nd edn. Springer, Boston, MACrossRefGoogle Scholar
  64. Wilson SR, Gerhold KA, Bifolck-Fisher A, Liu Q, Patel KN, Dong X, Bautista DM (2011) TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch. Nat Neurosci 14(5):595–602PubMedCentralPubMedCrossRefGoogle Scholar
  65. Wilson SR, Nelson AM, Batia L, Morita T, Estandian D, Owens DM, Lumpkin EA, Bautista DM (2013a) The ion channel TRPA1 is required for chronic itch. J Neurosci 33(22):9283–9294Google Scholar
  66. Wilson SR, Thé L, Batia LM, Beattie K, Katibah GE, McClain SP, Pellegrino M, Estandian DM, Bautista DM (2013b) The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell: 155(2):285–295Google Scholar
  67. Yohn JJ, Smith C, Stevens T, Morelli JG, Shurnas LR, Walchak SJ, Hoffman TA, Kelley KK, Escobedo-Morse A, Yanagisawa M (1994) Autoregulation of endothelin-1 secretion by cultured human keratinocytes via the endothelin B receptor. Biochim Biophys Acta 1224(3):454–458PubMedCrossRefGoogle Scholar
  68. Yoo J, Omori M, Gyarmati D, Zhou B, Aye T, Brewer A, Comeau MR, Campbell DJ, Ziegler SF (2005) Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin. J Exp Med 202(4):541–549PubMedCentralPubMedCrossRefGoogle Scholar
  69. Yu XJ, Li CY, Wang KY, Dai HY (2006) Calcitonin gene-related peptide regulates the expression of vascular endothelial growth factor in human HaCaT keratinocytes by activation of ERK1/2 MAPK. Regul Pept 137(3):134–139PubMedCrossRefGoogle Scholar
  70. Ziegler SF, Artis D (2010) Sensing the outside world: TSLP regulates barrier immunity. Nat Immunol 11(4):289–293PubMedCentralPubMedCrossRefGoogle Scholar
  71. Ziegler SF, Roan F, Bell BD, Stoklasek TA, Kitajima M, Han H (2013) The biology of thymic stromal lymphopoietin (TSLP). Adv Pharmacol 66:129–155PubMedCentralPubMedCrossRefGoogle Scholar
  72. Zylka MJ, Rice FL, Anderson DJ (2005) Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron 45(1):17–25PubMedCrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Department of Molecular and Cellular BiologyUniversity of California BerkeleyBerkeleyUSA

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