Improved metal allergen reactivity of artificial skin models by integration of TLR4‐positive cells
Verena G. Frings Damaris Müller Gabriel Storz Angela Rossi Helga Sennefelder Christian Adam Matthias Goebeler Florian K. Groeber‐Becker Marc Schmidt
First published: 14 June 2019 https://doi.org/10.1111/cod.13336
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/cod.13336.
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Abstract
Background
Reconstructed human epidermis (RhE) is widely employed to replace animal models to assess the proinflammatory and allergenic effects of chemicals. Unfortunately, RhE lacks proinflammatory responsiveness for metal haptens, the most relevant human contact allergens, raising concerns about their reliability to predict skin allergens.
Objectives
We investigated whether this limitation of RhE might be due to a lack of functional TLR4 expression that governs proinflammatory sensitivity to nickel and cobalt.
Materials and Methods
RhE, dendritic cell (DC)‐containing RhE and full‐thickness skin equivalents (FTSE) were compared regarding their proinflammatory responsiveness to metal allergens.
Results
We demonstrate that the incorporation of dermal fibroblasts is sufficient to confer metal sensitivity to RhE. Unlike keratinocytes, normal human fibroblasts expressed high levels of TLR4 mRNA and induced IL‐8 upon stimulation with nickel or cobalt. Consistently, dermal isolates from full‐thickness skin equivalents (FTSE) expressed considerable amounts of TLR4 mRNA whereas RhE or epidermis isolated from FTSE, normal or inflamed human epidermis failed to express TLR4. Similarly, co‐culture with TLR4‐positive DCs bestowed RhE with proinflammatory responsiveness to metals.
Conclusion
Our data suggest that FTSE or DC/RhE co‐culture models can circumvent shortcomings of RhE assays and combine benefits of complex and monoculture‐based test systems in a single assay.
Verena G. Frings Damaris Müller Gabriel Storz Angela Rossi Helga Sennefelder Christian Adam Matthias Goebeler Florian K. Groeber‐Becker Marc Schmidt
First published: 14 June 2019 https://doi.org/10.1111/cod.13336
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/cod.13336.
ePDFPDFTOOLS SHARE
Abstract
Background
Reconstructed human epidermis (RhE) is widely employed to replace animal models to assess the proinflammatory and allergenic effects of chemicals. Unfortunately, RhE lacks proinflammatory responsiveness for metal haptens, the most relevant human contact allergens, raising concerns about their reliability to predict skin allergens.
Objectives
We investigated whether this limitation of RhE might be due to a lack of functional TLR4 expression that governs proinflammatory sensitivity to nickel and cobalt.
Materials and Methods
RhE, dendritic cell (DC)‐containing RhE and full‐thickness skin equivalents (FTSE) were compared regarding their proinflammatory responsiveness to metal allergens.
Results
We demonstrate that the incorporation of dermal fibroblasts is sufficient to confer metal sensitivity to RhE. Unlike keratinocytes, normal human fibroblasts expressed high levels of TLR4 mRNA and induced IL‐8 upon stimulation with nickel or cobalt. Consistently, dermal isolates from full‐thickness skin equivalents (FTSE) expressed considerable amounts of TLR4 mRNA whereas RhE or epidermis isolated from FTSE, normal or inflamed human epidermis failed to express TLR4. Similarly, co‐culture with TLR4‐positive DCs bestowed RhE with proinflammatory responsiveness to metals.
Conclusion
Our data suggest that FTSE or DC/RhE co‐culture models can circumvent shortcomings of RhE assays and combine benefits of complex and monoculture‐based test systems in a single assay.
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