FOXO1 differentially regulates both normal and diabetic wound healing.
Healing is delayed in diabetic wounds. We previously demonstrated that lineage-specific Foxo1 deletion in keratinocytes interfered with normal wound healing and keratinocyte migration. Surprisingly, the same deletion of Foxo1 in diabetic wounds had the opposite effect, significantly improving the healing response. In normal glucose media, forkhead box O1 (FOXO1) enhanced keratinocyte migration through up-regulating TGFβ1. In high glucose, FOXO1 nuclear localization was induced but FOXO1 did not bind to the TGFβ1 promoter or stimulate TGFβ1 transcription. Instead, in high glucose, FOXO1 enhanced expression of serpin peptidase inhibitor, clade B (ovalbumin), member 2 (SERPINB2), and chemokine (C-C motif) ligand 20 (CCL20). The impact of high glucose on keratinocyte migration was rescued by silencing FOXO1, by reducing SERPINB2 or CCL20, or by insulin treatment. In addition, an advanced glycation end product and tumor necrosis factor had a similar regulatory effect on FOXO1 and its downstream targets and inhibited keratinocyte migration in a FOXO1-dependent manner. Thus, FOXO1 expression can positively or negatively modulate keratinocyte migration and wound healing by its differential effect on downstream targets modulated by factors present in diabetic healing.
Department of Preventive Dentistry, Peking University School and Hospital of Stomatology, Beijing 100081, China Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Chenying
C
Zhang
Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Bhaskar
B
Ponugoti
Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Chen
C
Tian
Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104 School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, China.
Fanxing
F
Xu
Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Rohinton
R
Tarapore
Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Angelika
A
Batres
Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Sarah
S
Alsadun
Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Jason
J
Lim
Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Guangyu
G
Dong
Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104 dtgraves@dental.upenn.edu.
Dana T
DT
Graves
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002465:Cell Movement; D002478:Cells, Cultured; D054418:Chemokine CCL20 / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000503:physiopathology*; D005260:Female; D005455:Fluorescent Antibody Technique; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology*
C493447:CCL20 protein, mouse; D054418:Chemokine CCL20; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007004:Hypoglycemic Agents; D007328:Insulin; D012333:RNA, Messenger; C522950:Serpinb1a protein, mouse; D015843:Serpins; D053773:Transforming Growth Factor beta1