title: Crosstalk between keratinocytes and T cells in a 3D microenvironment: a model to study inflammatory skin diseases.
abstract: The interaction between keratinocytes and immune cells plays a major role in the development of inflammatory skin diseases like psoriasis and atopic dermatitis. Pharmacological intervention to inhibit T cell-derived proinflammatory mediators is an effective therapy in the treatment of psoriasis. Here, we present a model to study the interaction between keratinocytes and T cells in a three-dimensional (3D) microenvironment, based on human skin equivalents populated with CD4+ T cells. T cell migration into the dermis initiated keratinocyte activation within 2 days, with hallmarks of a psoriasiform inflammation after 4 days. Expression of epidermal psoriasis marker genes was upregulated, and proinflammatory cytokines and chemokines were highly expressed. Disturbed epidermal differentiation was shown by downregulated filaggrin expression and involucrin expression in the spinous layer. These effects were mediated via soluble factors produced by the T cells. The psoriasiform inflammation was also observed using T helper type 1 (Th1)- and Th17-polarized CD4+ T cells. We validated our model by treatment with anti-inflammatory drugs that reduced the expression of proinflammatory cytokines and chemokines and suppressed the psoriasiform inflammation. We propose that our T cell-driven inflammatory skin equivalent model has potential to study the pathogenesis of inflammatory skin diseases and may serve as a preclinical screening tool for anti-inflammatory drugs.
authors.affiliation: Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Ellen H
authors.initials: EH
authors.lastname: van den Bogaard
authors.affiliation: Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Geuranne S
authors.initials: GS
authors.lastname: Tjabringa
authors.affiliation: Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Irma
authors.initials: I
authors.lastname: Joosten
authors.affiliation: Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Mieke
authors.initials: M
authors.lastname: Vonk-Bergers
authors.affiliation: Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: van Rijssen
authors.affiliation: Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Henk J
authors.initials: HJ
authors.lastname: Tijssen
authors.affiliation: Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Mirthe
authors.initials: M
authors.lastname: Erkens
authors.affiliation: Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. Electronic address: j.schalkwijk@derma.umcn.nl.
authors.forename: Joost
authors.initials: J
authors.lastname: Schalkwijk
authors.affiliation: Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. Electronic address: h.koenen@labgk.umcn.nl.
authors.forename: Hans J P M
authors.initials: HJPM
authors.lastname: Koenen
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology*; D018929:Cell Culture Techniques / Q000379:methods; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D003876:Dermatitis, Atopic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020405:Dermis / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D000091344:Filaggrin Proteins; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D061251:Primary Cell Culture; D011565:Psoriasis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020239:Receptor Cross-Talk / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; C000717249:FLG protein, human; D000091344:Filaggrin Proteins