Selective Deficiency of HIF-1 Alpha in Myeloid Cells Influences Secondary Intention Wound Healing in Mouse Skin

Abstract

Background

Hypoxia-inducible factor-1 (HIF-1) influences myeloid cell function. In this study we examined the role of myeloid cell HIF-1α on wound healing in vivo using a cell-specific knockout (KO) mouse model.

Materials and Methods

HIF-1α KO mice and wild-type (WT) controls received 8 mm full thickness dorsal dermal wounds. Wound dimensions were measured until full closure. Tissue was obtained from 3-day-old wounds for (immuno-)histochemical analysis. Production of interleukin-1β (IL-1β) and nitric oxide (NO) in response to lipopolysaccharide (LPS) and/or desferrioxamine (DFX) was examined in vitro.

Results

Early wound closure occurred significantly faster in HIF-1α KO mice than in WT mice. Wounds of KO mice contained similar numbers of neutrophils and macrophages, but more activated keratinocytes, consistent with accelerated re-epithelialization. Interestingly, while LPS and LPS+DFX elicited a similar IL-1β response in macrophages from the 2 mouse types, NO production was blunted in HIF-1α KO macrophages.

Conclusion

Absence of HIF-1α in myeloid cells accelerates the early phase of secondary intention wound healing in vivo. This may be associated with a deficient ability of myeloid cells to initiate an appropriate NO production response. Pharmacologic modulators of HIF-1α should be explored in situations with abnormal wound healing.

Keywords: Neutrophils, macrophages, hypoxia-inducible factor 1, alpha subunit, mice, knockout, wound healing