High glucose restraint of acetylcholine-induced keratinocyte epithelial-mesenchymal transition is mitigated by p38 inhibition

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...

Full description

Saved in:
Bibliographic Details
Main Authors: Tan, Mark Wei Yi, Tan, Wei Ren, Kong, Ze Qing, Toh, Jun Hong, Wee, Jonathan Wei Kiat, Teo, Erica Mei Ling, Cheng, Hong Sheng, Wang, Xiaomeng, Tan, Nguan Soon
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2022
Subjects:
Online Access:https://hdl.handle.net/10356/157036
Tags: Add Tag
No Tags, Be the first to tag this record!
Institution: Nanyang Technological University
Language: English
id sg-ntu-dr.10356-157036
record_format dspace
spelling sg-ntu-dr.10356-1570362023-02-28T17:12:02Z High glucose restraint of acetylcholine-induced keratinocyte epithelial-mesenchymal transition is mitigated by p38 inhibition Tan, Mark Wei Yi Tan, Wei Ren Kong, Ze Qing Toh, Jun Hong Wee, Jonathan Wei Kiat Teo, Erica Mei Ling Cheng, Hong Sheng Wang, Xiaomeng Tan, Nguan Soon School of Biological Sciences Lee Kong Chian School of Medicine (LKCMedicine) Interdisciplinary Graduate School (IGS) Institute of Molecular and Cell Biology, A*STAR Singapore Eye Research Institute NTU Institute for Health Technologies Science::Biological sciences Acetylcholine Cell Function 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. Ministry of Education (MOE) Submitted/Accepted version This research is supported by the Singapore Ministry of Education under its Singapore Ministry of Education Academic Research Fund Tier 1 (2014-T1-002-138-03) and Tier 2 (MOE2018-T2- 1-043) to NST. 2022-04-30T15:05:58Z 2022-04-30T15:05:58Z 2021 Journal Article Tan, M. W. Y., Tan, W. R., Kong, Z. Q., Toh, J. H., Wee, J. W. K., Teo, E. M. L., Cheng, H. S., Wang, X. & Tan, N. S. (2021). High glucose restraint of acetylcholine-induced keratinocyte epithelial-mesenchymal transition is mitigated by p38 inhibition. Journal of Investigative Dermatology, 141(6), 1438-1449. https://dx.doi.org/10.1016/j.jid.2020.10.026 0022-202X https://hdl.handle.net/10356/157036 10.1016/j.jid.2020.10.026 33333125 2-s2.0-85099163823 6 141 1438 1449 en 2014-T1-002-138-03 MOE2018-T2- 1-043 Journal of Investigative Dermatology © 2021 The Authors. All rights reserved. This paper was published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology in Journal of Investigative Dermatology and is made available with permission of The Authors. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Biological sciences
Acetylcholine
Cell Function
spellingShingle Science::Biological sciences
Acetylcholine
Cell Function
Tan, Mark Wei Yi
Tan, Wei Ren
Kong, Ze Qing
Toh, Jun Hong
Wee, Jonathan Wei Kiat
Teo, Erica Mei Ling
Cheng, Hong Sheng
Wang, Xiaomeng
Tan, Nguan Soon
High glucose restraint of acetylcholine-induced keratinocyte epithelial-mesenchymal transition is mitigated by p38 inhibition
description 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.
author2 School of Biological Sciences
author_facet School of Biological Sciences
Tan, Mark Wei Yi
Tan, Wei Ren
Kong, Ze Qing
Toh, Jun Hong
Wee, Jonathan Wei Kiat
Teo, Erica Mei Ling
Cheng, Hong Sheng
Wang, Xiaomeng
Tan, Nguan Soon
format Article
author Tan, Mark Wei Yi
Tan, Wei Ren
Kong, Ze Qing
Toh, Jun Hong
Wee, Jonathan Wei Kiat
Teo, Erica Mei Ling
Cheng, Hong Sheng
Wang, Xiaomeng
Tan, Nguan Soon
author_sort Tan, Mark Wei Yi
title High glucose restraint of acetylcholine-induced keratinocyte epithelial-mesenchymal transition is mitigated by p38 inhibition
title_short High glucose restraint of acetylcholine-induced keratinocyte epithelial-mesenchymal transition is mitigated by p38 inhibition
title_full High glucose restraint of acetylcholine-induced keratinocyte epithelial-mesenchymal transition is mitigated by p38 inhibition
title_fullStr High glucose restraint of acetylcholine-induced keratinocyte epithelial-mesenchymal transition is mitigated by p38 inhibition
title_full_unstemmed High glucose restraint of acetylcholine-induced keratinocyte epithelial-mesenchymal transition is mitigated by p38 inhibition
title_sort high glucose restraint of acetylcholine-induced keratinocyte epithelial-mesenchymal transition is mitigated by p38 inhibition
publishDate 2022
url https://hdl.handle.net/10356/157036
_version_ 1759853989767151616