Role of fibroblasts in the pathogenesis of atopic dermatitis

• Published in: Journal of allergy and clinical immunology Vol. 131; no. 6; pp. 1547 - 1554.e6
• Main Authors: Berroth, Andreas, Dipl-Ing, Kühnl, Jochen, PhD, Kurschat, Nina, PhD, Schwarz, Agatha, PhD, Stäb, Franz, PhD, Schwarz, Thomas, MD, Wenck, Horst, PhD, Fölster-Holst, Regina, MD, Neufang, Gitta, PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.06.2013; Elsevier; Elsevier Limited
• Subjects: Adult; Allergic diseases; Allergy and Immunology; Atopic dermatitis; Biological and medical sciences; Biopsy; Cell Differentiation; Cell Proliferation; Collagen; Dermatitis, Atopic - etiology; differentiation; Epidermis - metabolism; Epidermis - pathology; Female; fibroblast; Fibroblasts - metabolism; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene expression; Gene Expression Regulation; Humans; Immunopathology; Keratin; keratinocyte; Keratinocytes - cytology; leukemia inhibitory factor; Leukemia Inhibitory Factor - genetics; Leukemia Inhibitory Factor - metabolism; Male; Medical sciences; Middle Aged; Mutation; organotypic culture; Pathogenesis; Rodents; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Skin allergic diseases. Stinging insect allergies; stratification; Studies; Tissue Culture Techniques; Germany; Signal transducer and activator of transcription; differentiation; AD; stratification; Organotypic culture with healthy fibroblasts and atopic keratinocytes; Organotypic culture with atopic fibroblasts and atopic keratinocytes; Organotypic culture with healthy fibroblasts and healthy keratinocytes; LIF; Small interfering RNA; Suppressor of cytokine signaling 3; organotypic culture; siRNA; SOCS3; STAT; fibroblast; Atopic dermatitis; keratinocyte; leukemia inhibitory factor; FK-OTC; Organotypic culture with atopic fibroblasts and healthy keratinocytes; OTC; Allergy; Immunopathology; Skin disease; Pathogenesis; Leukemia inhibitory factor; Organotypic culture; Cell differentiation; Atopy; Immunology; Keratinocyte; Differentiation; Fibroblast
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2013.02.029

Background Atopic dermatitis (AD) is a common dermatosis that highly impairs a patient's quality of life. The recent discovery that epidermal barrier defects caused by an aberrant differentiation process of keratinocytes are comparably important to the well-characterized changes in immune response patterns attributed a crucial role to the keratinocytes. Fibroblasts are able to alter proliferation and differentiation of keratinocytes, but their role in AD is not yet fully understood. Objective We sought to determine the role of fibroblasts in skin proliferation and differentiation in patients with AD. Methods We used human 3-dimensional organotypic skin cultures consisting of atopic fibroblasts and healthy keratinocytes, as well as healthy fibroblasts and atopic keratinocytes, and compared them with their controls. The expression of differentiation markers in these organotypic cultures were analyzed by using immunohistology and quantitative RT-PCR. Furthermore, the fundamental role of fibroblast-secreted leukemia inhibitory factor was assessed by using small interfering RNA–mediated knockdown cultures. Results We observed that atopic fibroblasts influence the proliferation of keratinocytes and the terminal differentiation process, resulting in an in vivo –like morphology of AD. Subsequently, healthy fibroblasts were able to restore the structural deficits of the epidermis consisting of atopic keratinocytes. Partially, these effects were due to a reduced expression of the differentiation-associated cytokine leukemia inhibitory factor by atopic fibroblasts. Conclusion These data demonstrate that fibroblasts and the modulation of fibroblast-derived factors might be new therapeutic targets for the alleviation of AD.