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FOXO1 differentially regulates both normal and diabetic wound healing.


ABSTRACT: 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 TGF?1. In high glucose, FOXO1 nuclear localization was induced but FOXO1 did not bind to the TGF?1 promoter or stimulate TGF?1 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.

SUBMITTER: Zhang C 

PROVIDER: S-EPMC4411275 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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FOXO1 differentially regulates both normal and diabetic wound healing.

Zhang Chenying C   Ponugoti Bhaskar B   Tian Chen C   Xu Fanxing F   Tarapore Rohinton R   Batres Angelika A   Alsadun Sarah S   Lim Jason J   Dong Guangyu G   Graves Dana T DT  

The Journal of cell biology 20150401 2


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  ...[more]

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