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Title: MUTZ-3 derived Langerhans cells in human skin equivalents show differential migration and phenotypic plasticity after allergen or irritant exposure

After allergen or irritant exposure, Langerhans cells (LC) undergo phenotypic changes and exit the epidermis. In this study we describe the unique ability of MUTZ-3 derived Langerhans cells (MUTZ-LC) to display similar phenotypic plasticity as their primary counterparts when incorporated into a physiologically relevant full-thickness skin equivalent model (SE-LC). We describe differences and similarities in the mechanisms regulating LC migration and plasticity upon allergen or irritant exposure. The skin equivalent consisted of a reconstructed epidermis containing primary differentiated keratinocytes and CD1a{sup +} MUTZ-LC on a primary fibroblast-populated dermis. Skin equivalents were exposed to a panel of allergens and irritants. Topical exposure to sub-toxic concentrations of allergens (nickel sulfate, resorcinol, cinnamaldehyde) and irritants (Triton X-100, SDS, Tween 80) resulted in LC migration out of the epidermis and into the dermis. Neutralizing antibody to CXCL12 blocked allergen-induced migration, whereas anti-CCL5 blocked irritant-induced migration. In contrast to allergen exposure, irritant exposure resulted in cells within the dermis becoming CD1a{sup −}/CD14{sup +}/CD68{sup +} which is characteristic of a phenotypic switch of MUTZ-LC to a macrophage-like cell in the dermis. This phenotypic switch was blocked with anti-IL-10. Mechanisms previously identified as being involved in LC activation and migration in native human skin could thus bemore » reproduced in the in vitro constructed skin equivalent model containing functional LC. This model therefore provides a unique and relevant research tool to study human LC biology in situ under controlled in vitro conditions, and will provide a powerful tool for hazard identification, testing novel therapeutics and identifying new drug targets. - Highlights: • MUTZ-3 derived Langerhans cells integrated into skin equivalents are fully functional. • Anti-CXCL12 blocks allergen-induced MUTZ-LC migration. • Anti-CCL5 blocks irritant-induced MUTZ-LC migration. • Irritant mediated MUTZ-LC trans-differentiation to macrophage-like cell in dermis. • Trans-differentiation of MUTZ-LC is IL-10 dependent.« less
Authors:
;  [1] ;  [2] ;  [1] ;  [3]
  1. Department of Dermatology, VU University Medical Center, Amsterdam (Netherlands)
  2. Department of Dermatology Medical Oncology, VU University Medical Center, Amsterdam (Netherlands)
  3. (ACTA), Amsterdam (Netherlands)
Publication Date:
OSTI Identifier:
22465803
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 287; Journal Issue: 1; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTIBODIES; CHLOROPHYLL; CONCENTRATION RATIO; DENDRITES; DERMATITIS; EPIDERMIS; FIBROBLASTS; GROWTH FACTORS; HAZARDS; HUMAN POPULATIONS; IN VITRO; MACROPHAGES; NEOPLASMS; NICKEL SULFATES; PLASTICITY; RESORCINOL; SWITCHES; TOXICITY; TRITURUS