Hypoxia reveals the new function of Foxn1 in keratinocytes antioxidant defense system

Skin exposed to environmental threats including injuries and oxidative stress developed an efficient but not fully recognized systems of repair and antioxidant protection. In this project we provide evidence that Foxn1 in keratinocytes regulates elements of electron transport chain and participates in thioredoxin system (Txn2, Txnrd3, Srxn1) induction, particularly under hypoxic environment. It is shown that Foxn1 in keratinocytes upregulate glutathione thioredoxin reductase 3 (Txnrd3) protein, and high levels of Txnrd3 mRNA were detected in injured skin of Foxn1+/+ mice. It also shown that Foxn1 strongly downregulate CCN2 protein participating in reconstruction of the epidermis after injury. As in vitro assay revealed that Foxn1 controls keratinocytes migration stimulating it under normoxia and suppressing under hypoxia. Keratinocytes overexpressing Foxn1 and exposed to hypoxia showed reduced ability to promote angiogenesis by downregulation of Vegfa. In conclusion, this study showed a new mechanism in which Foxn1, along with hypoxia, participates in the activation of antioxidant defense and controls functional properties of keratinocytes.