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

Abstract

Skin, the largest organ of the body, serves as a protective barrier against infections, heat loss, dehydration, and mechanical insults and can sense external (temperature, touch) and internal (neurons, hormones) signals. 1,2 Interruption of skin integrity by injury or surgical intervention can lead to severe damage and abnormal homeostasis. 3 The integrity of the wounded skin is restored through a reparative healing process, which results in scar formation. Although scarring

Dermal White Adipose Tissue (dWAT) Is Regulated by Foxn1 and Hif-1α during the Early Phase of Skin Wound Healing

“…The similar pattern detected in the reduction levels of MIP-1γ and CD68 mRNA expression, particularly at post-wounding day 3, can indicate the role of the Foxn1/Hif-1α transgenes in the resolution of the inflammatory phase of the healing. The data are in agreement with our previous study that showed the extensive accumulation of CD68-positive cells and higher levels of monocyte chemoattractant protein 1 (MCP-1) in the wounded skin of Foxn1 −/− mice [ 39 ]. Whether Foxn1/Hif-1α, through macrophages content regulation, can contribute to skin wound healing, remains an important issue for future research.…”

“…The process of re-epithelialization was completed on day 6 for LV-empty/control- and LV-Foxn1+LV-Hif-1α-treated mice (100%; Figure 3 ). Our previous study showed 94% of re-epithelialization on post-wounding day 3, and completion of the process on day 5 during skin wound healing of Foxn1 −/− mice [ 39 ]. Observed discrepancies in the re-epithelialization pace between previous and present experiments are most likely caused by LVs injection, per se.…”

“…Our previous investigations showed that Foxn1 −/− mice displayed impairments in the regulation of Hif-1α during the skin wound healing process [ 39 ]. We also demonstrated that a decrease in Foxn1 activity is related to a resistance to diet-induced obesity in Foxn1 +/− mice, and that Foxn1 regulates dWAT capacity since Foxn1 +/− mice showed an altered expression of adipogenic genes in non-injured and post-injured skin [ 12 ].…”

“…Interestingly, in contrast to the well-known stimulatory effect of Hif-1α on proangiogenic pathways in white adipose tissues, Hif-1α transactivates genes, leading to extracellular matrix component accumulation and, finally, causing fibrosis and inflammatory cell infiltration [ 35 , 38 ]. Our recent data indicate that Foxn1 controls hypoxia-regulated factors [ 39 ]. The skin of wounded and unwounded Foxn1 −/− mice displayed low levels of Hif-1α expression that were unchanged by wounding, whereas Hif-1α expression was modulated in the wounded skin of Foxn1 +/+ mice [ 39 ].…”

“…Our recent data indicate that Foxn1 controls hypoxia-regulated factors [ 39 ]. The skin of wounded and unwounded Foxn1 −/− mice displayed low levels of Hif-1α expression that were unchanged by wounding, whereas Hif-1α expression was modulated in the wounded skin of Foxn1 +/+ mice [ 39 ]. In an in vitro study, the overexpression of Foxn1 led to the downregulation of Hif-1α mRNA at the expense of the upregulation of Fih-1 (factor inhibiting Hif-1α), indicating the possible mechanisms by which Foxn1 regulates hypoxia-related genes [ 39 ].…”