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.

The Role of Forkhead Box 1 (FOXO1) in the Immune System: Dendritic Cells, T Cells, B Cells, and Hematopoietic Stem Cells

“…76 For example, in normal wound healing, FOXO1 plays a positive role in promoting keratinocyte behavior to enhance healing, whereas diabetic conditions alter FOXO1-induced gene targets to inhibit healing. 77,78 Therefore, FOXO behavior may depend on the cell type and specific conditions, which is a cautionary tale in not extrapolating FOXO function from one cell type to another or one condition to another. This suggests that FOXOs are tightly regulated by epigenetic considerations, which is certain to be a highly investigated topic.…”

PKCδ inhibition normalizes the wound-healing capacity of diabetic human fibroblasts

“…oxidative stress. In the absence of FoxO1, there is increased oxidative damage, reduced TGF-β1 expression, reduced migration and proliferation of keratinocytes, and increased keratinocyte apoptosis, leading to impaired reepithelialization of wounds (46). We previously reported that hyperglycemia and angiotensin II (AngII), and possibly other causative factors such as oxidants and inflammatory cytokines, may play an important role in inducing selective insulin resistance and reducing the expression of VEGF and other cytokines (47).…”

Chondrocytes Promote Vascularization in Fracture Healing Through a FOXO1-Dependent Mechanism

“…Deletion of multiple FOXOs (FOXO1, FOXO3, and FOXO4) results in abnormal growth plate organization and skeletal abnormalities . In soft tissue healing deletion of FOXO1 in keratinocytes of normal wounds impairs re‐epithelialization whereas deletion of FOXO1 in keratinocytes of diabetic wounds accelerates it . This result suggests that in normal conditions FOXO1 acts to promote soft tissue wound healing.…”