RT Journal Article
SR Electronic
T1 Foxo1 Inhibits Diabetic Mucosal Wound Healing but Enhances Healing of Normoglycemic Wounds
JF Diabetes
JO Diabetes
FD American Diabetes Association
SP 243
OP 256
DO 10.2337/db14-0589
VO 64
IS 1
A1 Xu, Fanxing
A1 Othman, Badr
A1 Lim, Jason
A1 Batres, Angelika
A1 Ponugoti, Bhaskar
A1 Zhang, Chenying
A1 Yi, Leah
A1 Liu, Jian
A1 Tian, Chen
A1 Hameedaldeen, Alhassan
A1 Alsadun, Sarah
A1 Tarapore, Rohinton
A1 Graves, Dana T.
YR 2015
UL http://diabetes.diabetesjournals.org/content/64/1/243.abstract
AB 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.