Reduced FOXO1 Expression Accelerates Skin Wound Healing and Attenuates Scarring

Abstract

The forkhead box O (FOXO) family has been extensively investigated in aging and metabolism, but its role in tissue-repair processes remains largely unknown. Herein, we clarify the molecular aspect of the FOXO family in skin wound healing. We demonstrated that Foxo1 and Foxo3a were both up-regulated during murine skin wound healing. Partial knockout of Foxo1 in Foxo1(+/-) mice throughout the body led to accelerated skin wound healing with enhanced keratinocyte migration, reduced granulation tissue formation, and decreased collagen density, accompanied by an attenuated inflammatory response, but we observed no wound phenotype in Foxo3a(-/-) mice. Fibroblast growth factor 2, adiponectin, and notch1 genes were significantly increased at wound sites in Foxo1(+/-) mice, along with markedly altered extracellular signal-regulated kinase 1/2 and AKT phosphorylation. Similarly, transient knockdown of Foxo1 at the wound site by local delivery of antisense oligodeoxynucleotides enhanced skin wound healing. The link between FOXO1 and scarring extends to patients, in particular keloid scars, where we see FOXO1 expression markedly increased in fibroblasts and inflammatory cells within the otherwise normal dermis. This occurs in the immediate vicinity of the keloid by comparison to the center of the mature keloid, indicating that FOXO1 is associated with the overgrowth of this fibrotic response into adjacent normal skin. Overall, our data indicate that molecular targeting of FOXO1 may improve the quality of healing and reduce pathological scarring.

MiR-142 Is Required for Staphylococcus aureus Clearance at Skin Wound Sites via Small GTPase-Mediated Regulation of the Neutrophil Actin Cytoskeleton

“…The wound model was established as described previously (Mori et al, 2014). In brief, full-thickness excisional wounds (4-mm biopsy punch; Kai Industries, Seki, Japan) were made in the dorsal skin (after shaving under anesthesia) of 6-to 12-week-old mice (Figure 1b).…”

Genetic Basis of Irritant Susceptibility in Health Care Workers

“…FOXO transcription family is also known to be involved in wound healing. 59 The association of this SNP with ICD could be related to its overlap with these binding motifs. EGF, EGFR, and CXCL12 are known to play important roles in epithelial homeostasis and wound healing.…”

FOXN1 Transcription Factor in Epithelial Growth and Wound Healing

“…FOXN1 may function as a "pioneer" factor, which means that it has access to nucleosome-bound DNA, allowing other transcription factors to act at those sites and enabling pleiotropic transcriptional activity (23). Only two other FOX transcription factors, both from the FOXO subfamily, were implicated as regulators of the skin wound healing process, FOXO1 (24) and FOXO3 (25).…”