Stress Signals, Mediated by Membranous Glucocorticoid Receptor, Activate PLC/PKC/GSK-3β/β-catenin Pathway to Inhibit Wound Closure

• Type of Material: Article
• Authors: Ivan Jozic, University of Miami; Sasa Vukelic, Emory University; Olivera Stojadinovic, University of Miami; Liang Liang, University of Miami; Horacio A. Ramirez, University of Miami; Irena Pastar, University of Miami; Marjana Tomic Canic, University of Miami
• Language: English
• Date: 2017-05-01
• Publisher: Emory University Libraries
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jid.2016.11.036
• Title of Journal or Parent Work: Journal of Investigative Dermatology
• Volume: 137
• Issue: 5
• Start Page: 1144
• End Page: 1154
• Grant/Funding Information: This work was funded in part by 3M Healthcare Fellowship granted by Wound Healing Foundation (IJ), SAC Award SAC-2013-19 (MTC), NR008029 (MTC), and University of Miami Department of Dermatology and Cutaneous Surgery.
• Keywords: Receptors, Glucocorticoid; beta Catenin; Stress, Physiological; Signal Transduction; Cells, Cultured; Humans; Epithelial Cells; Glycogen Synthase Kinase 3 beta; Fibroblasts; Wnt Signaling Pathway; Protein Kinase C; Cell Movement; Keratinocytes; Wound Healing; Type C Phospholipases; Cell Line; Glucocorticoids
• Research Categories: Biology, Cell; Engineering, Biomedical; Biology, Molecular; Biology, Genetics; Health Sciences, Pharmacology

Abstract

Glucocorticoids (GCs), key mediators of stress signals, are also potent wound healing inhibitors. To understand how stress signals inhibit wound healing, we investigated the role of membranous glucocorticoid receptor (mbGR) by using cell-impermeable BSA-conjugated dexamethasone. We found that mbGR inhibits keratinocyte migration and wound closure by activating a Wnt-like phospholipase (PLC)/ protein kinase C (PKC) signaling cascade. Rapid activation of mbGR/PLC/PKC further leads to activation of known biomarkers of nonhealing found in patients, β-catenin and c-myc. Conversely, a selective inhibitor of PKC, calphostin C, blocks mbGR/PKC pathway, and rescues GC-mediated inhibition of keratinocyte migration in vitro and accelerates wound epithelialization of human wounds ex vivo. This novel signaling mechanism may have a major impact on understanding how stress response via GC signaling regulates homeostasis and its role in development and treatments of skin diseases, including wound healing. To test tissue specificity of this nongenomic signaling mechanism, we tested retinal and bronchial human epithelial cells and fibroblasts. We found that mbGR/PLC/PKC signaling cascade exists in all cell types tested, suggesting a more general role. The discovery of this nongenomic signaling pathway, in which glucocorticoids activate Wnt pathway via mbGR, provides new insights into how stress-mediated signals may activate growth signals in various epithelial and mesenchymal tissues.