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High Glucose Restraint of Acetylcholine-Induced Keratinocyte Epithelial-Mesenchymal Transition Is Mitigated by p38 Inhibition.

Authors
  • Tan, Mark Wei Yi1
  • Tan, Wei Ren2
  • Kong, Ze Qing3
  • Toh, Jun Hong3
  • Wee, Wei Kiat Jonathan3
  • Teo, Erica Mei Ling4
  • Cheng, Hong Sheng2
  • Wang, Xiaomeng5
  • Tan, Nguan Soon6
  • 1 School of Biological Sciences, Nanyang Technological University, Singapore, Singapore; NTU Institute for Health Technologies, Interdisciplinary Graduate School, Nanyang Technological University, Singapore, Singapore. , (Singapore)
  • 2 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore. , (Singapore)
  • 3 School of Biological Sciences, Nanyang Technological University, Singapore, Singapore. , (Singapore)
  • 4 NTU Institute for Health Technologies, Interdisciplinary Graduate School, Nanyang Technological University, Singapore, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore. , (Singapore)
  • 5 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore; Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore; Department of Cell Biology, Institute of Ophthalmology, University College London, London, United Kingdom; Singapore Eye Research Institute, The Academia, Singapore, Singapore. , (United Kingdom)
  • 6 School of Biological Sciences, Nanyang Technological University, Singapore, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore. Electronic address: [email protected] , (Singapore)
Type
Published Article
Journal
Journal of Investigative Dermatology
Publisher
Elsevier
Publication Date
Jun 01, 2021
Volume
141
Issue
6
Identifiers
DOI: 10.1016/j.jid.2020.10.026
PMID: 33333125
Source
Medline
Language
English
License
Unknown

Abstract

Non-neuronal acetylcholine (Ach) plays important roles in various aspects of cell biology and homeostasis outside the neural system. Keratinocytes (KCs) have a functional cholinergic mechanism, suggesting that they respond to Ach. However, the physiological role and mechanism by which Ach modulates wound KC behavior in both nondiabetic and diabetic conditions are unexplored. We found an enrichment in neurotransmitter-related pathways in microdissected-migrating nondiabetic and diabetic KCs. We showed that Ach upregulated TGFβRII through Src-extracellular signal‒regulated kinase 1/2 pathway to potentiate TGFβ1-mediated epithelial‒mesenchymal transition in normoglycemic condition. Unexpectedly, KCs were nonresponsive to the elevated endogenous Ach in a hyperglycemic environment. We further showed that the activation of p38 MAPK in high glucose condition interferes with Src-extracellular signal‒regulated kinase 1/2 signaling, resulting in Ach resistance that could be rescued by inhibiting p38 MAPK. A better understanding of the cholinergic physiology in diabetic KCs could improve wound management and care. The finding suggests that mitigating the inhibitory effect of diabetic wound microenvironment has a direct clinical implication on the efficacy and safety of various wound healing agents to improve chronic diabetic wounds. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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