AI Article Synopsis
- FOXO1 deletion in keratinocytes normally hinders wound healing but boosts healing in diabetic conditions, suggesting a complex role in different environments.
- In normal glucose, FOXO1 promotes keratinocyte migration by boosting TGFβ1 levels, while in high glucose, it fails to activate TGFβ1 and instead increases SERPINB2 and CCL20 expression.
- Targeting FOXO1 or its downstream effects can improve keratinocyte migration in high glucose situations, highlighting its dual regulatory role in diabetic wound healing.
Article 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 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4411275 | PMC |
| http://dx.doi.org/10.1083/jcb.201409032 | DOI Listing |
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