Impairment of the Hif-1; regulatory pathway in Foxn1-deficient (Foxn1-/-) mice affects the skin wound healing process

Abstract

Hypoxia and hypoxia-regulated factors [e. g., hypoxia-inducible factor-1 (Hif-1), factor inhibiting Hif-1 (Fih-1), thioredoxin-1 (Trx-1), aryl hydrocarbon receptor nuclear translocator 2 (Arnt-2)] have essential roles in skin wound healing. Using Foxn1-/- mice that can heal skin injuries in a unique scarless manner, we investigated the interaction between Foxn1 and hypoxia-regulated factors. The Foxn1-/- mice displayed impairments in the regulation of Hif-1, Trx-1 and Fih-1 but not Arnt-2 during the healing process. An analysis of wounded skin showed that the skin of the Foxn1-/- mice healed in a scarless manner, displaying rapid re-epithelialization and an increase in transforming growth factor {beta} (Tgf{beta}-3) and collagen III expression. An in vitro analysis revealed that Foxn1 overexpression in keratinocytes isolated from the skin of the Foxn1-/- mice led to reduced Hif-1 expression in normoxic but not hypoxic cultures and inhibited Fih-1 expression exclusively under hypoxic conditions. These data indicate that in the skin, Foxn1 affects hypoxia-regulated factors that control the wound healing process and suggest that under normoxic conditions, Foxn1 is a limiting factor for Hif-1.