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Published on: July 3, 2015
The δ-opioid receptor affects epidermal homeostasis via ERK-dependent inhibition of transcription factor POU2F3
Christine Neumann1, Mei Bigliardi-Qi2, Christian Widmann3
1Experimental Dermatology Laboratory, Institute of Medical Biology, A*STAR, Singapore; Doctoral School Faculty of Biology and Medicine, University of Lausanne, Dorigny, Switzerland; These authors contributed equally to this work.
Abstract:
Neuropeptides and their receptors are present in human skin, and their importance for cutaneous homeostasis and during wound healing is increasingly appreciated. However, there is currently a lack of understanding of the molecular mechanisms by which their signaling modulates keratinocyte function. Here, we show that δ-opioid receptor (DOPr) activation inhibits proliferation of human keratinocytes, resulting in decreased epidermal thickness in an organotypic skin model. DOPr signaling markedly delayed induction of keratin intermediate filament (KRT10) during in vitro differentiation and abolished its induction in the organotypic skin model. This was accompanied by deregulation of involucrin (IVL), loricrin, and filaggrin. Analysis of the transcription factor POU2F3, which is involved in regulation of KRT10, IVL, and profilaggrin expression, revealed a DOPr-mediated extracellular signal-regulated kinase (ERK)-dependent downregulation of this factor. We propose that DOPr signaling specifically activates the ERK 1/2 mitogen-activated protein kinase pathway to regulate keratinocyte functions. Complementing our earlier studies in DOPr-deficient mice, these data suggest that DOPr activation in human keratinocytes profoundly influences epidermal morphogenesis and homeostasis.
Insights
Activation of the delta-opioid receptor (DOPr) in human skin inhibits keratinocyte proliferation and differentiation, impacting epidermal thickness. This signaling pathway involves the ERK pathway and affects key epidermal proteins.
Area of Science:
- Dermatology
- Molecular Biology
- Cell Biology
Background:
- Neuropeptides and receptors are vital for skin homeostasis and wound healing.
- Mechanisms linking neuropeptide signaling to keratinocyte function are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanisms of delta-opioid receptor (DOPr) signaling in human keratinocytes.
- To investigate the impact of DOPr activation on epidermal development and homeostasis.
Main Methods:
- Organotypic skin models were used to study keratinocyte proliferation and differentiation.
- Analysis included keratin intermediate filament (KRT10), involucrin (IVL), loricrin, and filaggrin expression.
- Investigated the role of the transcription factor POU2F3 and the ERK pathway.
Main Results:
- DOPr activation inhibited human keratinocyte proliferation, reducing epidermal thickness.
- Delayed KRT10 induction and disrupted IVL, loricrin, and filaggrin expression were observed.
- DOPr signaling led to ERK-dependent downregulation of the transcription factor POU2F3.
Conclusions:
- DOPr signaling, via the ERK pathway, regulates keratinocyte function and epidermal morphogenesis.
- DOPr activation significantly influences human epidermal homeostasis.
- Findings complement studies in DOPr-deficient mice, highlighting the receptor's role in skin.
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