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.
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References
Miller RL, Peden DB (2014) Environmental effects on immune responses in patients with atopy and asthma. J Allergy Clin Immunol 134:1001–1008
Barnetson RS, Rogers M (2002) Childhood atopic eczema. BMJ 324:1376–1379
Correale CE, Walker C, Murphy L, Craig TJ (1999) Atopic dermatitis: a review of diagnosis and treatment. Am Fam Physician 60:1191–1198
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
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
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
Dubrac S, Schmuth M, Ebner S (2010) Atopic dermatitis: the role of Langerhans cells in disease pathogenesis. Immunol Cell Biol 88:400–409
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
Elias PM, Schmuth M (2009) Abnormal skin barrier in the etiopathogenesis of atopic dermatitis. Curr Opin Allergy Clin Immunol 9:437–446
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
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
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
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
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
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
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
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
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
Dahten A, Mergemeier S, Worm M (2007) PPARgamma expression profile and its cytokine driven regulation in atopic dermatitis. Allergy 62:926–933
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
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
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
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
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
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
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
Eyerich K, Novak N (2013) Immunology of atopic eczema: overcoming the Th1/Th2 paradigm. Allergy 68:974–982
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
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
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
Kim BS (2015) Innate lymphoid cells in the skin. J Invest Dermatol 135:673–678
Maintz L, Novak N (2011) Modifications of the innate immune system in atopic dermatitis. J Innate Immun 3:131–141
Hammad H, Lambrecht BN (2015) Barrier epithelial cells and the control of type 2 immunity. Immunity 43:29–40
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
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
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
Baker BS (2006) The role of microorganisms in atopic dermatitis. Clin Exp Immunol 144:1–9
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
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
Jin H, He R, Oyoshi M, Geha RS (2009) Animal models of atopic dermatitis. J Invest Dermatol 129:31–40
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
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
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
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
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
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
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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
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DOI: https://doi.org/10.1007/978-1-4939-6786-5_8
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