FOXO1, TGF-β regulation and wound healing

Abstract

Re-epithelialization is a complex process that involves migration and proliferation of keratinocytes, in addition to the production of cytokines and growth factors that affect other cells. The induction of transcription factors during these processes is crucial for successful wound healing. The transcription factor forkhead boxO-1 (FOXO1) has recently been found to be an important regulator of wound healing. In particular, FOXO1 has significant effects through regulation of transforming growth factor-beta (TGF-β) expression and protecting keratinocytes from oxidative stress. In the absence of FOXO1, there is increased oxidative damage, reduced TGF-β1 expression, reduced migration and proliferation of keratinocytes and increased keratinocytes apoptosis leading to impaired re-epithelialization of wounds.

Figure 1

(a) Oxidative stress increases in the inflammatory phase of wound healing. FOXO1 down-regulates oxidative stress by activating antioxidant genes and DNA repair enzymes. This facilitates keratinocyte migration and proliferation and decreases keratinocyte apoptosis, which improves wound healing; (b) FOXO1 stimulates TGF-β promoter activity resulting in the upregulation of TGF-β expression. Increased TGF-β stimulates expression of integrins and matrix metalloproteinases to improve wound healing through increased keratinocyte migration and decreased apoptosis.

Figure 2

In low glucose conditions, FOXO1 promotes wound healing by increasing TGF-β levels. This leads to an increase in keratinocyte migration and re-epithelialization. However, in high glucose conditions FOXO1 does not stimulate an increase in TGFβ1. Instead, FOXO1 increases inflammatory gene expression (increased CCL20), which interferes with keratinocyte migration. Thus, in standard glucose levels FOXO1 promotes healing but in high glucose FOXO1 is detrimental to healing by a switch in the genes that it regulates (see [44]).