Impairment of the Hif‐1α regulatory pathway in Foxn1‐deficient (Foxn1−/−) mice affects the skin wound healing process

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

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Bibliographic Details
Published in:The FASEB journal 2021-02, Vol.35 (2), p.e21289-n/a
Main Authors: Machcinska, Sylwia, Kopcewicz, Marta, Bukowska, Joanna, Walendzik, Katarzyna, Gawronska‐Kozak, Barbara
Format: Article
Language:English
Subjects:
Foxn1
Hif‐1α
hypoxia
scarless healing
skin
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Summary:Hypoxia and hypoxia‐regulated factors (eg, hypoxia‐inducible factor‐1α [Hif‐1α], factor inhibiting Hif‐1α [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‐1α, 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 β (Tgfβ‐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‐1α 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‐1α.
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.202001907R