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Interactions Between Keratinocytes and Somatosensory Neurons in Itch

  • Chapter
Pharmacology of Itch

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

Abstract

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.

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Abbreviations

AD:

Atopic dermatitis

CALCRL:

Calcitonin receptor-like receptor

CCL5:

Chemokine ligand 5

CGRP:

Calcitonin gene-related peptide

DRG:

Dorsal root ganglia

ER:

Endoplasmic reticulum

ET-1:

Endothelin-1

H1R:

Histamine 1 receptor

IL:

Interleukin

KLK:

Kallikrein

NFAT:

Nuclear factor of activated T cells

NGF:

Nerve growth factor

NK1R:

Neurokinin 1 receptor

ORAI1:

Calcium release-activated calcium channel protein 1

PAR2:

Protease-activated receptor 2

SLIGRL:

Ser–Leu–Iso–Gly–Arg–Leu

SP:

Substance P

TH2:

T helper type 2

TRPA1:

Transient receptor potential cation channel A1

TRPV1:

Transient receptor potential cation channel V1

TSLP:

Thymic stromal lymphopoietin

VCAM-1:

Vascular cellular adhesion molecule 1

References

  • 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):23–26

    Article  CAS  PubMed  Google Scholar 

  • Bautista DM, Wilson SR, Hoon MA (2014) Why we scratch an itch: the molecules, cells and circuits of itch. Nat Neurosci 17(2):175–182

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Boguniewicz M, Leung DYM (2011) Atopic dermatitis: a disease of altered skin barrier and immune dysregulation. Immunol Rev 242(1):233–246

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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):1135–1147

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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):448–460

    Google Scholar 

  • Chatterjea D, Martinov T (2014) Mast cells: versatile gatekeepers of pain. Mol Immunol: 63(1):38–44

    Google Scholar 

  • 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):251–263

    Article  CAS  PubMed  Google Scholar 

  • 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):21718–21722

    PubMed  Google Scholar 

  • 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):619–632

    Article  CAS  PubMed  Google Scholar 

  • Elias PM, Schmuth M (2009) Abnormal skin barrier in the etiopathogenesis of atopic dermatitis. Curr Allergy Asthma Rep 9(4):265–272

    Article  CAS  PubMed  Google Scholar 

  • Elmariah SB, Lerner EA (2011) Topical therapies for pruritus. Semin Cutan Med Surg 30(2):118–126

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Elmariah SB, Reddy VB, Lerner EA (2014) Cathepsin S signals via PAR2 and generates a novel tethered ligand receptor agonist. PLoS One 9(6):e99702

    Article  PubMed Central  PubMed  Google Scholar 

  • 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):499–513

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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):1403–1407

    Google Scholar 

  • Girardi M (2006) Immunosurveillance and immunoregulation by γδ T cells. J Investig Dermatol 126(1):25–31

    Article  CAS  PubMed  Google Scholar 

  • 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):1176–1182

    Article  CAS  PubMed  Google Scholar 

  • Gomes LO, Hara DB, Rae GA (2012) Endothelin-1 induces itch and pain in the mouse cheek model. Life Sci 91(13–14):628–633

    Article  CAS  PubMed  Google Scholar 

  • Gutowska-Owsiak D, Ogg GS (2012) Cytokine regulation of the epidermal barrier. Clin Exp Allergy: 43(6):586–598

    Google Scholar 

  • 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):174–182

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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):1824–1835

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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):134–137

    Google Scholar 

  • 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):605–610

    Article  CAS  PubMed  Google Scholar 

  • Ikoma A, Steinhoff M, Stander S, Yosipovitch G, Schmelz M (2006) The neurobiology of itch. Nat Rev Neurosci 7(7):535–547

    Article  CAS  PubMed  Google Scholar 

  • 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):11330–11335

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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):459–466

    Article  CAS  PubMed  Google Scholar 

  • Jeffry J, Kim S, Chen ZF (2011) Itch signaling in the nervous system. Physiology (Bethesda) 26(4):286–292

    Article  CAS  Google Scholar 

  • 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):614–619

    Article  CAS  PubMed  Google Scholar 

  • 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):3–11

    Article  PubMed  Google Scholar 

  • 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):1055–1061

    Article  CAS  PubMed  Google Scholar 

  • 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):2683–95

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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):159–162

    Article  CAS  PubMed  Google Scholar 

  • 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):1169–1176

    Article  PubMed  Google Scholar 

  • 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):170ra16

    Article  PubMed Central  PubMed  Google Scholar 

  • 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):34–41

    Article  CAS  PubMed  Google Scholar 

  • 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):513–519

    Article  CAS  PubMed  Google Scholar 

  • Leung DY (2013) New insights into atopic dermatitis: role of skin barrier and immune dysregulation. Allergol Int 62(2):151–161

    Article  CAS  PubMed  Google Scholar 

  • 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):14795–14800

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Liang J, Kawamata T, Ji W (2010) Molecular signaling of pruritus induced by endothelin-1 in mice. Exp Biol Med 235(11):1300–1305

    Article  CAS  Google Scholar 

  • 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):1353–1365

    Article  PubMed Central  PubMed  Google Scholar 

  • Lumpkin EA, Caterina MJ (2007) Mechanisms of sensory transduction in the skin. Nature 445(7130):858–865

    Article  CAS  PubMed  Google Scholar 

  • Malaviya R, Morrison AR, Pentland AP (1996) Histamine in human epidermal cells is induced by ultraviolet light injury. J Invest Dermatol 106(4):785–789

    Article  CAS  PubMed  Google Scholar 

  • 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):138–151

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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):930–937

    Article  CAS  PubMed  Google Scholar 

  • Patel T, Yosipovitch G (2010a) The management of chronic pruritus in the elderly. Skin Therapy Lett 15(8):5–9

    PubMed  Google Scholar 

  • Patel T, Yosipovitch G (2010b) Therapy of pruritus. Expert Opin Pharmacother 11(10):1673–1682

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Raap U, Stander S, Metz M (2011) Pathophysiology of itch and new treatments. Curr Opin Allergy Clin Immunol 11(5):420–427

    Article  CAS  PubMed  Google Scholar 

  • Raychaudhuri SP, Raychaudhuri SK (2004) Role of NGF and neurogenic inflammation in the pathogenesis of psoriasis. Prog Brain Res 146:433–437

    Article  CAS  PubMed  Google Scholar 

  • 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):1468–1470

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Richardson JD, Vasko MR (2002) Cellular mechanisms of neurogenic inflammation. J Pharmacol Exp Ther 302(3):839–845

    Article  CAS  PubMed  Google Scholar 

  • 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):1620–1628

    Article  CAS  PubMed  Google Scholar 

  • 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):9151–9155

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Simpson CL, Patel DM, Green KJ (2011) Deconstructing the skin: cytoarchitectural determinants of epidermal morphogenesis. Nat Rev Mol Cell Biol 12(9):565–580

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Siniewicz-LuzeÅ„czyk K, StaÅ„czyk-PrzyÅ‚uska A, Zeman K (2013) Correlation between serum interleukin 31 level and the severity of disease in children with atopic dermatitis. Adv Dermatol Allergol 5:282–285

    Article  Google Scholar 

  • 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):229–233

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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):673–680

    CAS  PubMed  Google Scholar 

  • 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):18–25

    Article  CAS  PubMed  Google Scholar 

  • 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):6176–6180

    CAS  PubMed  Google Scholar 

  • Tanaka RJ, Ono M, Harrington HA (2011) Skin barrier homeostasis in atopic dermatitis: feedback regulation of kallikrein activity. PLoS One 6(5):e19895

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tay SS, Roediger B, Tong PL, Tikoo S, Weninger W (2013) The skin-resident immune network. Curr Dermatol Rep 3(1):13–22

    Article  PubMed Central  PubMed  Google Scholar 

  • 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):71–79

    Article  CAS  PubMed  Google Scholar 

  • Urashima R, Mihara M (1998) Cutaneous nerves in atopic dermatitis. Virchows Arch 432(4):363–370

    Article  CAS  PubMed  Google Scholar 

  • 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):274–275

    Article  PubMed  Google Scholar 

  • Willis WD Jr, Coggeshall RE (1991) Sensory mechanisms of the spinal cord, 2nd edn. Springer, Boston, MA

    Book  Google Scholar 

  • 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):595–602

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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):9283–9294

    Google Scholar 

  • 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):285–295

    Google Scholar 

  • 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):454–458

    Article  PubMed  Google Scholar 

  • 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):541–549

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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):134–139

    Article  CAS  PubMed  Google Scholar 

  • Ziegler SF, Artis D (2010) Sensing the outside world: TSLP regulates barrier immunity. Nat Immunol 11(4):289–293

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ziegler SF, Roan F, Bell BD, Stoklasek TA, Kitajima M, Han H (2013) The biology of thymic stromal lymphopoietin (TSLP). Adv Pharmacol 66:129–155

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zylka MJ, Rice FL, Anderson DJ (2005) Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron 45(1):17–25

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Molecular and Cellular Biology, University of California Berkeley, 355 LSA MC#3200, Berkeley, CA, 94720-3200, USA

    Jamie Schwendinger-Schreck, Sarah R. Wilson & Diana M. Bautista

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  1. Jamie Schwendinger-Schreck
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  2. Sarah R. Wilson
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  3. Diana M. Bautista
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Correspondence to Diana M. Bautista .

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Editors and Affiliations

  1. Department of Pharmacology Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, Pennsylvania, USA

    Alan Cowan

  2. Department of Dermatology, Temple University School of Medicine, Philadephia, Pennsylvania, USA

    Gil Yosipovitch

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Schwendinger-Schreck, J., Wilson, S.R., Bautista, D.M. (2015). Interactions Between Keratinocytes and Somatosensory Neurons in Itch. In: Cowan, A., Yosipovitch, G. (eds) Pharmacology of Itch. Handbook of Experimental Pharmacology, vol 226. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-44605-8_10

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