Impairment Of The Hif-1 Alpha Regulatory Pathway In Foxn1-Deficient (Foxn1(-/-)) Mice Affects The Skin Wound Healing Process

Hypoxia and hypoxia-regulated factors (eg, hypoxia-inducible factor-1 alpha [Hif-1 alpha], factor inhibiting Hif-1 alpha [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 alpha, 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 alpha 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 alpha.