Foxo1 Inhibits Diabetic Mucosal Wound Healing but Enhances Healing of Normoglycemic Wounds

Re-epithelialization is an important part in mucosal wound healing. Surprisingly little is known about the impact of diabetes on the molecular events of mucosal healing. We examined the role of the transcription factor forkhead box O1 (Foxo1) in oral wounds of diabetic and normoglycemic mice with ke...

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Main Authors:	Xu, Fanxing, Othman, Badr, Lim, Jason, Batres, Angelika, Ponugoti, Bhaskar, Zhang, Chenying, Yi, Leah, Liu, Jian, Tian, Chen, Hameedaldeen, Alhassan, Alsadun, Sarah, Tarapore, Rohinton, Graves, Dana T.
Format:	Online
Language:	English
Published:	American Diabetes Association 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274809/

id	pubmed-4274809
recordtype	oai_dc
spelling	pubmed-42748092016-01-01 Foxo1 Inhibits Diabetic Mucosal Wound Healing but Enhances Healing of Normoglycemic Wounds Xu, Fanxing Othman, Badr Lim, Jason Batres, Angelika Ponugoti, Bhaskar Zhang, Chenying Yi, Leah Liu, Jian Tian, Chen Hameedaldeen, Alhassan Alsadun, Sarah Tarapore, Rohinton Graves, Dana T. Complications Re-epithelialization is an important part in mucosal wound healing. Surprisingly little is known about the impact of diabetes on the molecular events of mucosal healing. We examined the role of the transcription factor forkhead box O1 (Foxo1) in oral wounds of diabetic and normoglycemic mice with keratinocyte-specific Foxo1 deletion. Diabetic mucosal wounds had significantly delayed healing with reduced cell migration and proliferation. Foxo1 deletion rescued the negative impact of diabetes on healing but had the opposite effect in normoglycemic mice. Diabetes in vivo and in high glucose conditions in vitro enhanced expression of chemokine (C-C motif) ligand 20 (CCL20) and interleukin-36γ (IL-36γ) in a Foxo1-dependent manner. High glucose–stimulated Foxo1 binding to CCL20 and IL-36γ promoters and CCL20 and IL-36γ significantly inhibited migration of these cells in high glucose conditions. In normal healing, Foxo1 was needed for transforming growth factor-β1 (TGF-β1) expression, and in standard glucose conditions, TGF-β1 rescued the negative effect of Foxo1 silencing on migration in vitro. We propose that Foxo1 under diabetic or high glucose conditions impairs healing by promoting high levels of CCL20 and IL-36γ expression but under normal conditions, enhances it by inducing TGF-β1. This finding provides mechanistic insight into how Foxo1 mediates the impact of diabetes on mucosal wound healing. American Diabetes Association 2015-01 2014-09-03 /pmc/articles/PMC4274809/ /pubmed/25187373 http://dx.doi.org/10.2337/db14-0589 Text en © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Xu, Fanxing Othman, Badr Lim, Jason Batres, Angelika Ponugoti, Bhaskar Zhang, Chenying Yi, Leah Liu, Jian Tian, Chen Hameedaldeen, Alhassan Alsadun, Sarah Tarapore, Rohinton Graves, Dana T.
spellingShingle	Xu, Fanxing Othman, Badr Lim, Jason Batres, Angelika Ponugoti, Bhaskar Zhang, Chenying Yi, Leah Liu, Jian Tian, Chen Hameedaldeen, Alhassan Alsadun, Sarah Tarapore, Rohinton Graves, Dana T. Foxo1 Inhibits Diabetic Mucosal Wound Healing but Enhances Healing of Normoglycemic Wounds
author_facet	Xu, Fanxing Othman, Badr Lim, Jason Batres, Angelika Ponugoti, Bhaskar Zhang, Chenying Yi, Leah Liu, Jian Tian, Chen Hameedaldeen, Alhassan Alsadun, Sarah Tarapore, Rohinton Graves, Dana T.
author_sort	Xu, Fanxing
title	Foxo1 Inhibits Diabetic Mucosal Wound Healing but Enhances Healing of Normoglycemic Wounds
title_short	Foxo1 Inhibits Diabetic Mucosal Wound Healing but Enhances Healing of Normoglycemic Wounds
title_full	Foxo1 Inhibits Diabetic Mucosal Wound Healing but Enhances Healing of Normoglycemic Wounds
title_fullStr	Foxo1 Inhibits Diabetic Mucosal Wound Healing but Enhances Healing of Normoglycemic Wounds
title_full_unstemmed	Foxo1 Inhibits Diabetic Mucosal Wound Healing but Enhances Healing of Normoglycemic Wounds
title_sort	foxo1 inhibits diabetic mucosal wound healing but enhances healing of normoglycemic wounds
description	Re-epithelialization is an important part in mucosal wound healing. Surprisingly little is known about the impact of diabetes on the molecular events of mucosal healing. We examined the role of the transcription factor forkhead box O1 (Foxo1) in oral wounds of diabetic and normoglycemic mice with keratinocyte-specific Foxo1 deletion. Diabetic mucosal wounds had significantly delayed healing with reduced cell migration and proliferation. Foxo1 deletion rescued the negative impact of diabetes on healing but had the opposite effect in normoglycemic mice. Diabetes in vivo and in high glucose conditions in vitro enhanced expression of chemokine (C-C motif) ligand 20 (CCL20) and interleukin-36γ (IL-36γ) in a Foxo1-dependent manner. High glucose–stimulated Foxo1 binding to CCL20 and IL-36γ promoters and CCL20 and IL-36γ significantly inhibited migration of these cells in high glucose conditions. In normal healing, Foxo1 was needed for transforming growth factor-β1 (TGF-β1) expression, and in standard glucose conditions, TGF-β1 rescued the negative effect of Foxo1 silencing on migration in vitro. We propose that Foxo1 under diabetic or high glucose conditions impairs healing by promoting high levels of CCL20 and IL-36γ expression but under normal conditions, enhances it by inducing TGF-β1. This finding provides mechanistic insight into how Foxo1 mediates the impact of diabetes on mucosal wound healing.
publisher	American Diabetes Association
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274809/
_version_	1613170093474185216

Foxo1 Inhibits Diabetic Mucosal Wound Healing but Enhances Healing of Normoglycemic Wounds

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