Myeloid cells -like macrophages and neutrophils- are commonly found in infected/inflamed and ischemic tissues, areas that are characterized by restricted oxygen availability. A rapid adaptation to these hypoxic conditions is achieved through the activation of hypoxia inducible factor (HIF) signaling pathways.

The stability of the transcription factor HIF is regulated by prolyl-4-hydroxylase domain (PHD) enzymes in an oxygen-dependent manner. Under normoxic conditions PHDs utilize molecular oxygen to mark the a-subunit for proteasomal degradation. Contrary, under hypoxia, HIF-a is stabilized and modulates hypoxia-dependent cell functions. As PHDs are druggable targets and myeloid cells play an important role in hypoxia associated diseases we established myeloid specific PHD2 knock-out mice to analyze the impact of PHD2 on myeloid cell functions.

In vitro characterization of PHD2-deficient macrophages showed normoxic stabilization of HIF-a resulting in the induction of target genes like Glut1 and PHD3. While metabolism, polarization or phagocytosis were unchanged, the motility of PHD2-deficient macrophages was significantly reduced. Additionally, the expression of pro-angiogenic factors was increased compared to that of wild type macrophages. In a model of hind-limb ischemia we examined whether this altered macrophage phenotype is beneficial or unfavourable in vivo. Histology of the ischemic muscle of myeloid-specific PHD2 knock-out animals showed prolonged signs of inflammation and tissue repair. In line, limb perfusion as measured by Doppler Sonography revealed a stronger increase in reperfusion between day 7 and 21 post-surgery pointing to an ongoing hyperstimulation of capillaries. These results point to an important role of PHD2 for myeloid cell functions during ischemia.