Mutations in the gene encoding for filaggrin (FLG) are major predisposing factors for atopic dermatitis (AD). Besides genetic predisposition, immunological dysregulations considerably contribute to its pathophysiology. For example, thymic stromal lymphopoietin (TSLP) is highly expressed in lesional atopic skin and significantly contributes to the pathogenesis of AD by activating dendritic cells that then initiate downstream effects on, for example, T cells. However, little is known about the direct interplay between TSLP, filaggrin-deficient skin and other immune cells such as T lymphocytes. In the present study, FLG knockdown skin equivalents, characterised by intrinsically high TSLP levels, were exposed to activated CD4+ T cells. T cell exposure resulted in an inflammatory phenotype of the skin equivalents. Furthermore, a distinct shift from a Th1/Th17 to a Th2/Th22 profile was observed following exposure of T cells to filaggrin-deficient skin equivalents. Interestingly, TSLP directly stimulated T cell migration exclusively in filaggrin-deficient skin equivalents even in the absence of dendritic cells, indicating a hitherto unknown role of TSLP in the pathogenesis of AD.

Department of Veterinary Medicine Institute of Veterinary Pathology Freie Universität Berlin Berlin Germany

Faculty of Pharmacy Charles University Prague Hradec Kralove Czech Republic

Institute for Pharmacy Pharmacology and Toxicology Freie Universität Berlin Berlin Germany

Institute of Nutritional Science Department of Toxicology University of Potsdam Potsdam Germany

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Pickett K, Frampton G, Loveman E. Education to improve quality of life of people with chronic inflammatory skin conditions: a systematic review of the evidence. Br J Dermatol. 2016;174:1228–1241. doi: 10.1111/bjd.14435. PubMed DOI

Bieber T. Atopic dermatitis. N Engl J Med. 2008;358:1483–1494. doi: 10.1056/NEJMra074081. PubMed DOI

Novak N, Leung DY. Advances in atopic dermatitis. Curr Opin Immunol. 2011;23:778–783. doi: 10.1016/j.coi.2011.09.007. PubMed DOI PMC

Proksch E, Fölster-Holst R, Jensen JM. Skin barrier function, epidermal proliferation and differentiation in eczema. J Dermatol Sci. 2006;43:159–169. doi: 10.1016/j.jdermsci.2006.06.003. PubMed DOI

Janssens M, et al. Lamellar lipid organization and ceramide composition in the stratum corneum of patients with atopic eczema. J Invest Dermatol. 2011;131:2136–2138. doi: 10.1038/jid.2011.175. PubMed DOI

Palmer CN, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006;38:441–446. doi: 10.1038/ng1767. PubMed DOI

Brown SJ, McLean WH. One remarkable molecule: filaggrin. J Invest Dermatol. 2012;132:751–762. doi: 10.1038/jid.2011.393. PubMed DOI PMC

McAleer MA, Irvine AD. The multifunctional role of filaggrin in allergic skin disease. J Allergy Clin Immunol. 2013;131:280–291. doi: 10.1016/j.jaci.2012.12.668. PubMed DOI

Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med. 2011;365:1315–1327. doi: 10.1056/NEJMra1011040. PubMed DOI

Howell MD, et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol. 2009;124:R7–R12. doi: 10.1016/j.jaci.2009.07.012. PubMed DOI

Morizane, S. et al. TH2 cytokines increase kallikrein 7 expression and function in patients with atopic dermatitis. J Allergy Clin Immunol. 130, 259–261 e251 (2012). PubMed PMC

Danso MO, et al. TNF-alpha and Th2 cytokines induce atopic dermatitis-like features on epidermal differentiation proteins and stratum corneum lipids in human skin equivalents. J Invest Dermatol. 2014;134:1941–1950. doi: 10.1038/jid.2014.83. PubMed DOI

Hönzke S, et al. Influence of Th2 Cytokines on the Cornified Envelope, Tight Junction Proteins, and β-Defensins in Filaggrin-Deficient Skin Equivalents. J Invest Dermatol. 2016;136:631–639. doi: 10.1016/j.jid.2015.11.007. PubMed DOI

Peng W, Novak N. Pathogenesis of atopic dermatitis. Clin Exp Allergy. 2015;45:566–574. doi: 10.1111/cea.12495. PubMed DOI

Werfel T, et al. Cellular and molecular immunologic mechanisms in patients with atopic dermatitis. J Allergy Clin Immunol. 2016;138:336–349. doi: 10.1016/j.jaci.2016.06.010. PubMed DOI

Miazgowicz MM, Headley MB, Larson RP, Ziegler SF. Thymic stromal lymphopoietin and the pathophysiology of atopic disease. Expert Rev Clin Immunol. 2009;5:547–556. doi: 10.1586/eci.09.45. PubMed DOI PMC

Ziegler SF. The role of thymic stromal lymphopoietin (TSLP) in allergic disorders. Curr Opin Immunol. 2010;22:795–799. doi: 10.1016/j.coi.2010.10.020. PubMed DOI PMC

Nygaard U, et al. TSLP, IL-31, IL-33 and sST2 are new biomarkers in endophenotypic profiling of adult and childhood atopic dermatitis. J Eur Acad Dermatol Venereol. 2016;30:1930–1938. PubMed

Soumelis V, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol. 2002;3:673–680. doi: 10.1038/nrm910. PubMed DOI

Wilson SR, et al. The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell. 2013;155:285–295. doi: 10.1016/j.cell.2013.08.057. PubMed DOI PMC

Zhong J, et al. TSLP signaling pathway map: a platform for analysis of TSLP-mediated signaling. Database (Oxford). 2014;2014:bau007. doi: 10.1093/database/bau007. PubMed DOI PMC

Kashiwagi, M. et al. Direct control of regulatory T cells by keratinocytes. Nat Immunol (2017). PubMed PMC

Watanabe N, et al. Human thymic stromal lymphopoietin promotes dendritic cell-mediated CD4+ T cell homeostatic expansion. Nat Immunol. 2004;5:426–434. doi: 10.1038/ni1048. PubMed DOI

Ebner S, et al. Thymic stromal lymphopoietin converts human epidermal Langerhans cells into antigen-presenting cells that induce proallergic T cells. J Allergy Clin Immunol. 2007;119:982–990. doi: 10.1016/j.jaci.2007.01.003. PubMed DOI

Wang, Q. et al. Thymic stromal lymphopoietin signaling in CD4(+) T cells is required for TH2 memory. J Allergy Clin Immunol. 135, 781–791 e783 (2015). PubMed PMC

Kim BS, et al. TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation. Sci Transl Med. 2013;5:170ra116. doi: 10.1126/scitranslmed.3005374. PubMed DOI PMC

Kamsteeg M, et al. Type 2 helper T-cell cytokines induce morphologic and molecular characteristics of atopic dermatitis in human skin equivalent. Am J Pathol. 2011;178:2091–2099. doi: 10.1016/j.ajpath.2011.01.037. PubMed DOI PMC

Vávrová K, et al. Filaggrin deficiency leads to impaired lipid profile and altered acidification pathways in a 3D skin construct. J Invest Dermatol. 2014;134:746–753. doi: 10.1038/jid.2013.402. PubMed DOI

Masopust D, Schenkel JM. The integration of T cell migration, differentiation and function. Nat Rev Immunol. 2013;13:309–320. doi: 10.1038/nri3442. PubMed DOI

Pasparakis M, Haase I, Nestle FO. Mechanisms regulating skin immunity and inflammation. Nat Rev Immunol. 2014;14:289–301. doi: 10.1038/nri3646. PubMed DOI

Kuo IH, Yoshida T, De Benedetto A, Beck LA. The cutaneous innate immune response in patients with atopic dermatitis. J Allergy Clin Immunol. 2013;131:266–278. doi: 10.1016/j.jaci.2012.12.1563. PubMed DOI

Mu Z, et al. Molecular biology of atopic dermatitis. Clin Rev Allergy Immunol. 2014;47:193–218. doi: 10.1007/s12016-014-8415-1. PubMed DOI

Ito T, et al. TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J Exp Med. 2005;202:1213–1223. doi: 10.1084/jem.20051135. PubMed DOI PMC

Comeau MR, Ziegler SF. The influence of TSLP on the allergic response. Mucosal Immunol. 2010;3:138–147. doi: 10.1038/mi.2009.134. PubMed DOI

Bang K, et al. CD4+CD8+ (thymocyte-like) T lymphocytes present in blood and skin from patients with atopic dermatitis suggest immune dysregulation. Br J Dermatol. 2001;144:1140–1147. doi: 10.1046/j.1365-2133.2001.04223.x. PubMed DOI

Thyssen JP, Kezic S. Causes of epidermal filaggrin reduction and their role in the pathogenesis of atopic dermatitis. J Allergy Clin Immunol. 2014;134:792–799. doi: 10.1016/j.jaci.2014.06.014. PubMed DOI

Dajnoki Z, et al. Immune-mediated Skin Inflammation is Similar in Severe Atopic Dermatitis Patients With or Without Filaggrin Mutation. Acta Derm Venereol. 2016;96:645–650. doi: 10.2340/00015555-2272. PubMed DOI

Pellerin L, et al. Defects of filaggrin-like proteins in both lesional and nonlesional atopic skin. J Allergy Clin Immunol. 2013;131:1094–1102. doi: 10.1016/j.jaci.2012.12.1566. PubMed DOI

Gutowska-Owsiak D, et al. IL-17 downregulates filaggrin and affects keratinocyte expression of genes associated with cellular adhesion. Exp Dermatol. 2012;21:104–110. doi: 10.1111/j.1600-0625.2011.01412.x. PubMed DOI

Cornelissen, C. et al. IL-31 regulates differentiation and filaggrin expression in human organotypic skin models. J Allergy Clin Immunol. 129, 426–433, 433.e421–428 (2012). PubMed

Nygaard, U. et al. The “Alarmins” HMBG1 and IL-33 Downregulate Structural Skin Barrier Proteins and Impair Epidermal Growth. Acta Derm Venereol (2016). PubMed

Kim, J. H. et al. Thymic stromal lymphopoietin downregulates filaggrin expression by signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase (ERK) phosphorylation in keratinocytes. J Allergy Clin Immunol. 136, 205–208 e209 (2015). PubMed

Eberlein-König B, et al. Skin surface pH, stratum corneum hydration, trans-epidermal water loss and skin roughness related to atopic eczema and skin dryness in a population of primary school children. Acta Derm Venereol. 2000;80:188–191. doi: 10.1080/000155500750042943. PubMed DOI

Kim BE, Leung DY, Boguniewicz M, Howell MD. Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6. Clin Immunol. 2008;126:332–337. doi: 10.1016/j.clim.2007.11.006. PubMed DOI PMC

Koch PJ, et al. Lessons from loricrin-deficient mice: compensatory mechanisms maintaining skin barrier function in the absence of a major cornified envelope protein. J Cell Biol. 2000;151:389–400. doi: 10.1083/jcb.151.2.389. PubMed DOI PMC

Presland RB, et al. Loss of normal profilaggrin and filaggrin in flaky tail (ft/ft) mice: an animal model for the filaggrin-deficient skin disease ichthyosis vulgaris. J Invest Dermatol. 2000;115:1072–1081. doi: 10.1046/j.1523-1747.2000.00178.x. PubMed DOI

Furuse M, et al. Claudin-based tight junctions are crucial for the mammalian epidermal barrier: a lesson from claudin-1-deficient mice. J Cell Biol. 2002;156:1099–1111. doi: 10.1083/jcb.200110122. PubMed DOI PMC

Maier T, Guell M, Serrano L. Correlation of mRNA and protein in complex biological samples. FEBS Lett. 2009;583:3966–3973. doi: 10.1016/j.febslet.2009.10.036. PubMed DOI

Koussounadis A, et al. Relationship between differentially expressed mRNA and mRNA-protein correlations in a xenograft model system. Sci Rep. 2015;5:10775. doi: 10.1038/srep10775. PubMed DOI PMC

Edfors F, et al. Gene-specific correlation of RNA and protein levels in human cells and tissues. Molecular systems biology. 2016;12:883. doi: 10.15252/msb.20167144. PubMed DOI PMC

Wallmeyer L, et al. Stimulation of PPARalpha normalizes the skin lipid ratio and improves the skin barrier of normal and filaggrin deficient reconstructed skin. J Dermatol Sci. 2015;80:102–110. doi: 10.1016/j.jdermsci.2015.09.012. PubMed DOI

Küchler S, Strüver K, Friess W. Reconstructed skin models as emerging tools for drug absorption studies. Expert Opin Drug Metab Toxicol. 2013;9:1255–1263. doi: 10.1517/17425255.2013.816284. PubMed DOI

Tatsuno K, et al. TSLP Directly Interacts with Skin-Homing Th2 Cells Highly Expressing its Receptor to Enhance IL-4 Production in Atopic Dermatitis. J Invest Dermatol. 2015;135:3017–3024. doi: 10.1038/jid.2015.318. PubMed DOI

Leonard WJ. TSLP: finally in the limelight. Nat Immunol. 2002;3:605–607. doi: 10.1038/ni0702-605. PubMed DOI

Ziegler SF, Liu YJ. Thymic stromal lymphopoietin in normal and pathogenic T cell development and function. Nat Immunol. 2006;7:709–714. doi: 10.1038/ni1360. PubMed DOI

He R, et al. TSLP acts on infiltrating effector T cells to drive allergic skin inflammation. Proc Natl Acad Sci USA. 2008;105:11875–11880. doi: 10.1073/pnas.0801532105. PubMed DOI PMC

Al-Shami A, et al. A role for thymic stromal lymphopoietin in CD4(+) T cell development. J Exp Med. 2004;200:159–168. doi: 10.1084/jem.20031975. PubMed DOI PMC

Homey B, Steinhoff M, Ruzicka T, Leung DY. Cytokines and chemokines orchestrate atopic skin inflammation. J Allergy Clin Immunol. 2006;118:178–189. doi: 10.1016/j.jaci.2006.03.047. PubMed DOI

Massacand JC, et al. Helminth products bypass the need for TSLP in Th2 immune responses by directly modulating dendritic cell function. Proc Natl Acad Sci USA. 2009;106:13968–13973. doi: 10.1073/pnas.0906367106. PubMed DOI PMC

Roan F, et al. The multiple facets of thymic stromal lymphopoietin (TSLP) during allergic inflammation and beyond. J Leukoc Biol. 2012;91:877–886. doi: 10.1189/jlb.1211622. PubMed DOI PMC

Kitajima M, Lee HC, Nakayama T, Ziegler SF. TSLP enhances the function of helper type 2 cells. Eur J Immunol. 2011;41:1862–1871. doi: 10.1002/eji.201041195. PubMed DOI PMC

Toda M, et al. Polarized in vivo expression of IL-11 and IL-17 between acute and chronic skin lesions. Journal of Allergy and Clinical Immunology. 2003;111:875–881. doi: 10.1067/mai.2003.1414. PubMed DOI

Koga C, et al. Possible pathogenic role of Th17 cells for atopic dermatitis. J Invest Dermatol. 2008;128:2625–2630. doi: 10.1038/jid.2008.111. PubMed DOI

Bonefeld CM, et al. Epidermal filaggrin deficiency mediates increased systemic T-helper 17 immune response. Br J Dermatol. 2016;175:706–712. doi: 10.1111/bjd.14570. PubMed DOI

Guttman-Yassky E, et al. Low expression of the IL-23/Th17 pathway in atopic dermatitis compared to psoriasis. J Immunol. 2008;181:7420–7427. doi: 10.4049/jimmunol.181.10.7420. PubMed DOI PMC

Nograles, K. E. et al. IL-22-producing “T22” T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells. J Allergy Clin Immunol. 123, 1244–1252 e1242 (2009). PubMed PMC

Stark HJ, et al. Organotypic keratinocyte cocultures in defined medium with regular epidermal morphogenesis and differentiation. J Invest Dermatol. 1999;112:681–691. doi: 10.1046/j.1523-1747.1999.00573.x. PubMed DOI

van den Bogaard EH, et al. Crosstalk between keratinocytes and T cells in a 3D microenvironment: a model to study inflammatory skin diseases. J Invest Dermatol. 2014;134:719–727. doi: 10.1038/jid.2013.417. PubMed DOI

Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Meth. 2012;9:671–675. doi: 10.1038/nmeth.2089. PubMed DOI PMC

Schreml S, et al. Luminescent dual sensors reveal extracellular pH-gradients and hypoxia on chronic wounds that disrupt epidermal repair. Theranostics. 2014;4:721–735. doi: 10.7150/thno.9052. PubMed DOI PMC

Schäfer-Korting M, et al. The use of reconstructed human epidermis for skin absorption testing: Results of the validation study. Altern Lab Anim. 2008;36:161–187. PubMed

OECD, T. G. 428: Skin absorption: in vitro Method. OECD Guidelines for the Testing of Chemicals, Section. 4 (2004).