Skip to main content

A Mouse Model for Atopic Dermatitis Using Topical Application of Vitamin D3 or of Its Analog MC903

  • Protocol
  • First Online:
Inflammation

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1559))

Abstract

Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease with pruritus and high prevalence. Indeed, 15–30 % of children and 2–10 % of adults from industrialized countries are affected. Acute AD lesions are characterized by epidermal hyperplasia associated with a dominant Th2/Th17 immune response and dermal inflammatory infiltrates. Moreover, the expression of alarmins such as TSLP, IL-33, and IL-25 is upregulated in acute AD lesions. Topical application of vitamin D3 or of its low-calcemic analog MC903 induces changes in skin morphology and inflammation resembling immune perturbations observed in acute lesions of patients with AD. Mice treated with MC903 or vitamin D3 additionally display increased serum IgE levels, as observed in patients with extrinsic AD. Interestingly, these symptoms are not dependent on mouse gender or on genetic background. Thus, the easiness of this mouse model renders it very attractive to study immunologic abnormalities involved in AD development or maintenance. Furthermore, this model might be useful for preclinical studies aiming at unraveling new therapeutic strategies to treat AD. In this chapter, we describe the induction and major features of MC903 and vitamin D3-induced AD-like inflammation in mice.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 99.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Miller RL, Peden DB (2014) Environmental effects on immune responses in patients with atopy and asthma. J Allergy Clin Immunol 134:1001–1008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Barnetson RS, Rogers M (2002) Childhood atopic eczema. BMJ 324:1376–1379

    Article  PubMed  PubMed Central  Google Scholar 

  3. Correale CE, Walker C, Murphy L, Craig TJ (1999) Atopic dermatitis: a review of diagnosis and treatment. Am Fam Physician 60:1191–1198

    CAS  PubMed  Google Scholar 

  4. Yoshida K, Kubo A, Fujita H, Yokouchi M, Ishii K, Kawasaki H, Nomura T, Shimizu H, Kouyama K, Ebihara T, Nagao K, Amagai M (2014) Distinct behavior of human Langerhans cells and inflammatory dendritic epidermal cells at tight junctions in patients with atopic dermatitis. J Allergy Clin Immunol 134:856–864

    Article  PubMed  Google Scholar 

  5. Elentner A, Finke D, Schmuth M, Chappaz S, Ebner S, Malissen B, Kissenpfennig A, Romani N, Dubrac S (2009) Langerhans cells are critical in the development of atopic dermatitis-like inflammation and symptoms in mice. J Cell Mol Med 13:2658–2672

    Article  PubMed  Google Scholar 

  6. Nakajima S, Igyártó BZ, Honda T, Egawa G, Otsuka A, Hara-Chikuma M, Watanabe N, Ziegler SF, Tomura M, Inaba K, Miyachi Y, Kaplan DH, Kabashima K (2012) Langerhans cells are critical in epicutaneous sensitization with protein antigen via thymic stromal lymphopoietin receptor signaling. J Allergy Clin Immunol 129:1048–1055.e1046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Dubrac S, Schmuth M, Ebner S (2010) Atopic dermatitis: the role of Langerhans cells in disease pathogenesis. Immunol Cell Biol 88:400–409

    Article  PubMed  Google Scholar 

  8. Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, DeBenedetto A, Schneider L, Beck LA, Barnes KC, Leung DY (2009) Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol 124:R7–R12

    Article  CAS  PubMed  Google Scholar 

  9. Elias PM, Schmuth M (2009) Abnormal skin barrier in the etiopathogenesis of atopic dermatitis. Curr Opin Allergy Clin Immunol 9:437–446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Elias PM, Feingold KR (2001) Does the tail wag the dog? Role of the barrier in the pathogenesis of inflammatory dermatoses and therapeutic implications. Arch Dermatol 137:1079–1081

    CAS  PubMed  Google Scholar 

  11. Chorro L, Sarde A, Li M, Woollard KJ, Chambon P, Malissen B, Kissenpfennig A, Barbaroux JB, Groves R, Geissmann F (2009) Langerhans cell (LC) proliferation mediates neonatal development, homeostasis, and inflammation-associated expansion of the epidermal LC network. J Exp Med 206:3089–3100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kelleher M, Dunn-Galvin A, Hourihane JO, Murray D, Campbell LE, McLean WH, Irvine AD (2015) Skin barrier dysfunction measured by transepidermal water loss at 2 days and 2 months predates and predicts atopic dermatitis at 1 year. J Allergy Clin Immunol 135:930–935.e931

    Article  PubMed  PubMed Central  Google Scholar 

  13. Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, O’Regan GM, Watson RM, Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, Fleckman P, Lewis-Jones S, Arseculeratne G, Sergeant A, Munro CS, El Houate B, McElreavey K, Halkjaer LB, Bisgaard H, Mukhopadhyay S, McLean WH (2006) Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 38:441–446

    Article  CAS  PubMed  Google Scholar 

  14. Paternoster L, Standl M, Chen CM, Ramasamy A, Bønnelykke K, Duijts L, Ferreira MA, Alves AC, Thyssen JP, Albrecht E, Baurecht H, Feenstra B, Sleiman PM, Hysi P, Warrington NM, Curjuric I, Myhre R, Curtin JA, Groen-Blokhuis MM, Kerkhof M, Sääf A, Franke A, Ellinghaus D, Fölster-Holst R, Dermitzakis E, Montgomery SB, Prokisch H, Heim K, Hartikainen AL, Pouta A, Pekkanen J, Blakemore AI, Buxton JL, Kaakinen M, Duffy DL, Madden PA, Heath AC, Montgomery GW, Thompson PJ, Matheson MC, Le Souëf P, Australian Asthma Genetics Consortium (AAGC), St. Pourcain B, Smith GD, Henderson J, Kemp JP, Timpson NJ, Deloukas P, Ring SM, Wichmann HE, Müller-Nurasyid M, Novak N, Klopp N, Rodríguez E, McArdle W, Linneberg A, Menné T, Nohr EA, Hofman A, Uitterlinden AG, van Duijn CM, Rivadeneira F, de Jongste JC, van der Valk RJ, Wjst M, Jogi R, Geller F, Boyd HA, Murray JC, Kim C, Mentch F, March M, Mangino M, Spector TD, Bataille V, Pennell CE, Holt PG, Sly P, Tiesler CM, Thiering E, Illig T, Imboden M, Nystad W, Simpson A, Hottenga JJ, Postma D, Koppelman GH, Smit HA, Söderhäll C, Chawes B, Kreiner-Møller E, Bisgaard H, Melén E, Boomsma DI, Custovic A, Jacobsson B, Probst-Hensch NM, Palmer LJ, Glass D, Hakonarson H, Melbye M (2012) Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis. Nat Genet 44:187–192

    Article  CAS  Google Scholar 

  15. Weidinger S, Willis-Owen SA, Kamatani Y, Baurecht H, Morar N, Liang L, Edser P, Street T, Rodriguez E, O’Regan GM, Beattie P, Fölster-Holst R, Franke A, Novak N, Fahy CM, Winge MC, Kabesch M, Illig T, Heath S, Söderhäll C, Melén E, Pershagen G, Kere J, Bradley M, Lieden A, Nordenskjold M, Harper JI, McLean WH, Brown SJ, Cookson WO, Lathrop GM, Irvine AD, Moffatt MF (2013) A genome-wide association study of atopic dermatitis identifies loci with overlapping effects on asthma and psoriasis. Hum Mol Genet 22:4841–4856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gruber R, Elias PM, Crumrine D, Lin TK, Brandner JM, Hachem JP, Presland RB, Fleckman P, Janecke AR, Sandilands A, McLean WH, Fritsch PO, Mildner M, Tschachler E, Schmuth M (2011) Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function. Am J Pathol 178:2252–2263

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kezic S, O’Regan GM, Yau N, Sandilands A, Chen H, Campbell LE, Kroboth K, Watson R, Rowland M, McLean WH, Irvine AD (2011) Levels of filaggrin degradation products are influenced by both filaggrin genotype and atopic dermatitis severity. Allergy 66:934–940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Brown SJ, Kroboth K, Sandilands A, Campbell LE, Pohler E, Kezic S, Cordell HJ, McLean WH, Irvine AD (2012) Intragenic copy number variation within filaggrin contributes to the risk of atopic dermatitis with a dose-dependent effect. J Invest Dermatol 132:98–104

    Article  CAS  PubMed  Google Scholar 

  19. Dahten A, Mergemeier S, Worm M (2007) PPARgamma expression profile and its cytokine driven regulation in atopic dermatitis. Allergy 62:926–933

    Article  CAS  PubMed  Google Scholar 

  20. Koro O, Furutani K, Hide M, Yamada S, Yamamoto S (1999) Chemical mediators in atopic dermatitis: involvement of leukotriene B4 released by a type I allergic reaction in the pathogenesis of atopic dermatitis. J Allergy Clin Immunol 103:663–670

    Article  CAS  PubMed  Google Scholar 

  21. Janssens M, van Smeden J, Gooris GS, Bras W, Portale G, Caspers PJ, Vreeken RJ, Hankemeier T, Kezic S, Wolterbeek R, Lavrijsen AP, Bouwstra JA (2012) Increase in short-chain ceramides correlates with an altered lipid organization and decreased barrier function in atopic eczema patients. J Lipid Res 53:2755–2766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. van Smeden J, Janssens M, Kaye EC, Caspers PJ, Lavrijsen AP, Vreeken RJ, Bouwstra JA (2014) The importance of free fatty acid chain length for the skin barrier function in atopic eczema patients. Exp Dermatol 23:45–52

    Article  PubMed  Google Scholar 

  23. Suárez-Fariñas M, Tintle SJ, Shemer A, Chiricozzi A, Nograles K, Cardinale I, Duan S, Bowcock AM, Krueger JG, Guttman-Yassky E (2011) Nonlesional atopic dermatitis skin is characterized by broad terminal differentiation defects and variable immune abnormalities. J Allergy Clin Immunol 127:954–964.e951–954

    Article  PubMed  PubMed Central  Google Scholar 

  24. Rebane A, Zimmermann M, Aab A, Baurecht H, Koreck A, Karelson M, Abram K, Metsalu T, Pihlap M, Meyer N, Fölster-Holst R, Nagy N, Kemeny L, Kingo K, Vilo J, Illig T, Akdis M, Franke A, Novak N, Weidinger S, Akdis CA (2012) Mechanisms of IFN-γ-induced apoptosis of human skin keratinocytes in patients with atopic dermatitis. J Allergy Clin Immunol 129:1297–1306

    Article  CAS  PubMed  Google Scholar 

  25. Gruber R, Börnchen C, Rose K, Daubmann A, Volksdorf T, Wladykowski E, Vidal-Y-Sy S, Peters EM, Danso M, Bouwstra JA, Hennies HC, Moll I, Schmuth M, Brandner JM (2015) Diverse regulation of Claudin-1 and Claudin-4 in atopic dermatitis. Am J Pathol 185(10):2777–2789

    Article  CAS  PubMed  Google Scholar 

  26. Mansouri Y, Guttman-Yassky E (2015) Immune pathways in atopic dermatitis, and definition of biomarkers through broad and targeted therapeutics. J Clin Med 4(5):858–873

    Article  PubMed  PubMed Central  Google Scholar 

  27. Eyerich K, Novak N (2013) Immunology of atopic eczema: overcoming the Th1/Th2 paradigm. Allergy 68:974–982

    Article  CAS  PubMed  Google Scholar 

  28. Clausen ML, Jungersted JM, Andersen PS, Slotved HC, Krogfelt KA, Agner T (2013) Human β-defensin-2 as a marker for disease severity and skin barrier properties in atopic dermatitis. Br J Dermatol 169:587–593

    Article  CAS  PubMed  Google Scholar 

  29. Goo J, Ji JH, Jeon H, Kim MJ, Jeon SY, Cho MY, Lee SH, Choi EH (2010) Expression of antimicrobial peptides such as LL-37 and hBD-2 in nonlesional skin of atopic individuals. Pediatr Dermatol 27:341–348

    Article  PubMed  Google Scholar 

  30. Dhingra N, Suárez-Fariñas M, Fuentes-Duculan J, Gittler JK, Shemer A, Raz A, Fischetti VA, Krueger JG, Guttman-Yassky E (2013) Attenuated neutrophil axis in atopic dermatitis compared to psoriasis reflects TH17 pathway differences between these diseases. J Allergy Clin Immunol 132:498–501.e493

    Article  CAS  PubMed  Google Scholar 

  31. Kim BS (2015) Innate lymphoid cells in the skin. J Invest Dermatol 135:673–678

    Article  CAS  PubMed  Google Scholar 

  32. Maintz L, Novak N (2011) Modifications of the innate immune system in atopic dermatitis. J Innate Immun 3:131–141

    Article  CAS  PubMed  Google Scholar 

  33. Hammad H, Lambrecht BN (2015) Barrier epithelial cells and the control of type 2 immunity. Immunity 43:29–40

    Article  CAS  PubMed  Google Scholar 

  34. Tintle S, Shemer A, Suárez-Fariñas M, Fujita H, Gilleaudeau P, Sullivan-Whalen M, Johnson-Huang L, Chiricozzi A, Cardinale I, Duan S, Bowcock A, Krueger JG, Guttman-Yassky E (2011) Reversal of atopic dermatitis with narrow-band UVB phototherapy and biomarkers for therapeutic response. J Allergy Clin Immunol 128:583–593.e581–584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gittler JK, Shemer A, Suárez-Fariñas M, Fuentes-Duculan J, Gulewicz KJ, Wang CQ, Mitsui H, Cardinale I, de Guzman Strong C, Krueger JG, Guttman-Yassky E (2012) Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. J Allergy Clin Immunol 130:1344–1354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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 RR, Bazan F, Kastelein RA, Liu YJ (2002) Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 3:673–680

    Article  CAS  PubMed  Google Scholar 

  37. Baker BS (2006) The role of microorganisms in atopic dermatitis. Clin Exp Immunol 144:1–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Salimi M, Barlow JL, Saunders SP, Xue L, Gutowska-Owsiak D, Wang X, Huang LC, Johnson D, Scanlon ST, McKenzie AN, Fallon PG, Ogg GS (2013) A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis. J Exp Med 210:2939–2950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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 5:170ra116

    Article  Google Scholar 

  40. Jin H, He R, Oyoshi M, Geha RS (2009) Animal models of atopic dermatitis. J Invest Dermatol 129:31–40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Li M, Hener P, Zhang Z, Kato S, Metzger D, Chambon P (2006) Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis. Proc Natl Acad Sci U S A 103:11736–11741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Li M, Hener P, Zhang Z, Ganti KP, Metzger D, Chambon P (2009) Induction of thymic stromal lymphopoietin expression in keratinocytes is necessary for generating an atopic dermatitis upon application of the active vitamin D3 analogue MC903 on mouse skin. J Invest Dermatol 129:498–502

    Article  CAS  PubMed  Google Scholar 

  43. Leyva-Castillo JM, Hener P, Jiang H, Li M (2013) TSLP produced by keratinocytes promotes allergen sensitization through skin and thereby triggers atopic march in mice. J Invest Dermatol 133:154–163

    Article  CAS  PubMed  Google Scholar 

  44. Zhang Z, Hener P, Frossard N, Kato S, Metzger D, Li M, Chambon P (2009) Thymic stromal lymphopoietin overproduced by keratinocytes in mouse skin aggravates experimental asthma. Proc Natl Acad Sci U S A 106:1536–1541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wang Q, Du J, Zhu J, Yang X, Zhou B (2015) Thymic stromal lymphopoietin signaling in CD4(+) T cells is required for TH2 memory. J Allergy Clin Immunol 135:781–791.e783

    Article  CAS  PubMed  Google Scholar 

  46. Rebane A, Runnel T, Aab A, Maslovskaja J, Rückert B, Zimmermann M, Plaas M, Kärner J, Treis A, Pihlap M, Haljasorg U, Hermann H, Nagy N, Kemeny L, Erm T, Kingo K, Li M, Boldin MP, Akdis CA (2014) MicroRNA-146a alleviates chronic skin inflammation in atopic dermatitis through suppression of innate immune responses in keratinocytes. J Allergy Clin Immunol 134:836–847.e811

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sandrine Dubrac .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Science+Business Media LLC

About this protocol

Cite this protocol

Moosbrugger-Martinz, V., Schmuth, M., Dubrac, S. (2017). A Mouse Model for Atopic Dermatitis Using Topical Application of Vitamin D3 or of Its Analog MC903. In: Clausen, B., Laman, J. (eds) Inflammation. Methods in Molecular Biology, vol 1559. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6786-5_8

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-6786-5_8

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-6784-1

  • Online ISBN: 978-1-4939-6786-5

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics