title: The δ-opioid receptor affects epidermal homeostasis via ERK-dependent inhibition of transcription factor POU2F3.
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.
authors.affiliation: Experimental 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.
authors.forename: Christine
authors.initials: C
authors.lastname: Neumann
authors.affiliation: Experimental Dermatology Laboratory, Institute of Medical Biology, A*STAR, Singapore. Electronic address: mei.bigliardi@gmail.com.
authors.forename: Mei
authors.initials: M
authors.lastname: Bigliardi-Qi
authors.affiliation: Department of Physiology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Widmann
authors.affiliation: Experimental Dermatology Laboratory, Institute of Medical Biology, A*STAR, Singapore; Division of Rheumatology, University Medicine Cluster, National University Hospital, Singapore. Electronic address: paul.bigliardi@imb.a-star.edu.sg.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Bigliardi
mesh_terms: D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004817:Epidermis / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D000091344:Filaggrin Proteins; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology; D050810:Octamer Transcription Factors / Q000037:antagonists & inhibitors* / Q000502:physiology; D017465:Receptors, Opioid, delta / Q000502:physiology*
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D050810:Octamer Transcription Factors; C484169:POU2F3 protein, human; D017465:Receptors, Opioid, delta; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium