Universität zu Köln

Akasaka, Eijiro, Kleiser, Svenja ORCID: 0000-0003-2448-1710, Sengle, Gerhard, Bruckner-Tuderman, Leena and Nystroem, Alexander (2021). High Glucose Restraint of Acetylcholine-Induced Keratinocyte Epithelial-Mesenchymal Transition Is Mitigated by p38 Inhibition. J. Invest. Dermatol., 141 (6). S. 1450 - 1470. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1523-1747

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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 neurotransmitterrelated pathways in microdissected-migrating nondiabetic and diabetic KCs. We showed that Ach upregulated TGFbRII through Src-extracellular signal-regulated kinase 1/2 pathway to potentiate TGFb1-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Akasaka, Eijiro UNSPECIFIED UNSPECIFIED UNSPECIFIED Kleiser, Svenja UNSPECIFIED orcid.org/0000-0003-2448-1710 UNSPECIFIED Sengle, Gerhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Bruckner-Tuderman, Leena UNSPECIFIED UNSPECIFIED UNSPECIFIED Nystroem, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-575383
DOI:	10.1016/j.jid.2020.10.024
Journal or Publication Title:	J. Invest. Dermatol.
Volume:	141
Number:	6
Page Range:	S. 1450 - 1470
Date:	2021
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1523-1747
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RECESSIVE DYSTROPHIC EPIDERMOLYSIS; TGF-BETA; SKIN; MATRIX; FIBROBLASTS; FIBROSIS; GROWTH; MATRIX-METALLOPROTEINASE-9; PIRFENIDONE; ACTIVATION Multiple languages Dermatology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/57538