Loss of Epithelial Hypoxia-Inducible Factor Prolyl Hydroxylase 2 Accelerates Skin Wound Healing in Mice

Abstract

f Skin wound healing in mammals is a complex, multicellular process that depends on the precise supply of oxygen. Hypoxia-inducible factor (HIF) prolyl hydroxylase 2 (PHD2) serves as a crucial oxygen sensor and may therefore play an important role during reepithelialization. Hence, this study was aimed at understanding the role of PHD2 in cutaneous wound healing using different lines of conditionally deficient mice specifically lacking PHD2 in inflammatory, vascular, or epidermal cells. Interestingly, PHD2 deficiency only in keratinocytes and not in myeloid or endothelial cells was found to lead to faster wound closure, which involved enhanced migration of the hyperproliferating epithelium. We demonstrate that this effect relies on the unique expression of ␤ 3 -integrin in the keratinocytes around the tip of the migrating tongue in an HIF1␣-dependent manner. Furthermore, we show enhanced proliferation of these cells in the stratum basale, which is directly related to their attenuated transforming growth factor ␤ signaling. Thus, loss of the central oxygen sensor PHD2 in keratinocytes stimulates wound closure by prompting skin epithelial cells to migrate and proliferate. Inhibition of PHD2 could therefore offer novel therapeutic opportunities for the local treatment of cutaneous wounds.

A distinct regulatory region of the Bmp5 locus activates gene expression following adult bone fracture or soft tissue injury

“…Targeted disruption of HIF-1α in osteoblasts, keratinocytes, or Club cells results in impaired healing of bone or skin [79, 80], or asthma [81]. In contrast, increased HIF-1α expression or HIF-1α stabilization has been shown to improve regeneration in both bone and skin [79, 82]. Transcription factor activator protein-1 (AP-1) mediates gene transcription in response to cytokines and growth factors [83], and AP-1 family members like Fos and Jun are upregulated in response to many types of tissue injury [84–89].…”

Hypoxia-dependent regulation of inflammatory pathways in immune cells

“…While our understanding of the role of HIF hydroxylases in the regulation of immune cell function is far from complete, recent studies investigating individual HIF hydroxylase isoforms in discreet immune and epithelial cell subtypes have identified isoform-specific roles (80)(81)(82)(83)(84)(85)(86)(87)(88)(89). Notably, these phenotypes are not fully accounted for by downstream HIF-dependent effects, further supporting the existence of alternative hydroxylase-regulated pathways such as NF-κB in immune cells.…”

“…Interestingly, the expression of these enzymes was reported to be altered in inflammatory bowel disease, where the intestinal barrier is significantly perturbed (85)(86)(87). In keratinocytes, loss of PHD2 alters cell migration and subsequent wound healing in a HIF-dependent manner (88). In lymphocytes, loss of PHD2 is associated with altered cytokine production and immune activity (89).…”

Impairment of hypoxia-induced HIF-1α signaling in keratinocytes and fibroblasts by sulfur mustard is counteracted by a selective PHD-2 inhibitor

“…The results are given as the percentage of change in mRNA expression relative to control cells grown under normoxic conditions (N) set as 100 %. Data represent the mean ± SD of triplicate measurements (n = 3); ****P < 0.0001, ***P < 0.001, *P < 0.05 associated with accelerated wound healing in these animals (Kalucka et al 2013;Zhang et al 2013;Zimmermann et al 2014). Previously, topical application of SM in mice was shown to cause hyperglycemia by a mechanism involving direct inhibition of glycolysis in keratinocytes (Martens and Smith 2008;Sugendran et al 1992) that may result in enhanced PHD activity and reduced HIF-1α levels in the cells (Dehne et al 2010).…”