title: Foxo1 inhibits diabetic mucosal wound healing but enhances healing of normoglycemic wounds.
abstract: 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.
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Fanxing
authors.initials: F
authors.lastname: Xu
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Badr
authors.initials: B
authors.lastname: Othman
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Jason
authors.initials: J
authors.lastname: Lim
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Angelika
authors.initials: A
authors.lastname: Batres
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Ponugoti
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA Department of Preventive Dentistry, Peking University School and Hospital of Stomatology, Beijing, China.
authors.forename: Chenying
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Leah
authors.initials: L
authors.lastname: Yi
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA Department of Stomatology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Chen
authors.initials: C
authors.lastname: Tian
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Alhassan
authors.initials: A
authors.lastname: Hameedaldeen
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Alsadun
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Rohinton
authors.initials: R
authors.lastname: Tarapore
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA dtgraves@dental.upenn.edu.
authors.forename: Dana T
authors.initials: DT
authors.lastname: Graves
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D054418:Chemokine CCL20 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D006943:Hyperglycemia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D007375:Interleukin-1 / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology; D018345:Mice, Knockout; D009061:Mouth Mucosa / Q000473:pathology / Q000503:physiopathology*; D009504:Neutrophils / Q000473:pathology / Q000502:physiology; D061251:Primary Cell Culture; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology*
chemical_list: D001786:Blood Glucose; C493447:CCL20 protein, mouse; D054418:Chemokine CCL20; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C569167:IL1F9 protein, mouse; D007375:Interleukin-1; D053773:Transforming Growth Factor beta1