In vitro reproduction of clinical hallmarks of eczematous dermatitis in organotypic skin models.
Dermatitis is a group of highly pruritic chronic inflammatory skin diseases which represents a major public-health problem worldwide. The prevalence of dermatitis has increased in recent years affecting up to 20% of the general population. Acute skin lesions are characterized by extensive degrees of intercellular edema of the epidermis (spongiosis) and a marked perivenular inflammatory cell infiltrate in the dermis. Keratinocytes within eczematous lesions exhibit a modified expression of proinflammatory cytokines, chemokines and cell-surface molecules. The pathophysiological puzzle of dermatitis is far from being elucidated completely, but skin infiltration of activated memory/effector T cells are thought to play the pivotal role in the pathogeneses. The aim of this study was the set-up of organotypic models mimicking the symptoms of eczematous dermatitis to provide a tool for therapeutic research in vitro. Therefore activated T cells (ATs) were integrated in organotypic skin and epidermis equivalents (SE, EE). These models enabled the reproduction of several clinical hallmarks of eczematous dermatitis: (1) T cells induce keratinocyte apoptosis, which leads to a reduced expression of the adhesion molecule E-cadherin (E-cad) and disruption of the epidermal barrier. (2) Expression of intercellular adhesion molecule-1 (ICAM-1) allows the attachment of leukocytes to epidermal cells. (3) Upregulation of neurotrophin-4 (NT-4) in the epidermis is thought to mediate pruritus in lesions by supporting nerve outgrowth. (4) Elevated levels of pro-inflammatory cytokines (IL-1alpha and IL-6) and chemokines (IL-8, IP-10, TARC, MCP-1, RANTES and eotaxin) amplify the inflammatory response and lead to an influx of secondary immunocells into the skin. The therapeutics dexamethasone and FK506 markedly reduce cytokines/chemokines production and epidermal damaging in these models. These data underline that activated memory/effector T cells induce eczematous changes in this HaCaT cell based organotypic skin equivalent. Furthermore it can be concluded that these models make it possible to investigate targets of therapeutics in skin.
Engelhart
Karin
K
BioTeSys GmbH, Schelztorstrasse 54-56, 73728 Esslingen, Germany. k.engelhart@biotesys.de
El Hindi
Tarek
T
Biesalski
Hans-Konrad
HK
Pfitzner
Inka
I
D016207:Cytokines / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology; D004485:Eczema / Q000209:etiology* / Q000628:therapy; D017097:Electric Impedance; D006801:Humans; D007156:Immunologic Memory; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D015603:Keratinocytes / Q000473:pathology*; D017493:Leukocyte Common Antigens / Q000032:analysis; D008213:Lymphocyte Activation; D009414:Nerve Growth Factors / Q000032:analysis; D012867:Skin / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology*; D016559:Tacrolimus / Q000494:pharmacology
D016207:Cytokines; D009414:Nerve Growth Factors; D018799:Intercellular Adhesion Molecule-1; D003907:Dexamethasone; D017493:Leukocyte Common Antigens; C073922:neurotrophin 4; D016559:Tacrolimus