Hypoxia-Inducible Factors as Essential Regulators of Inflammation

Myeloid cells provide important functions in low oxygen (O-2) environments created by pathophysiological conditions, including sites of infection, inflammation, tissue injury, and solid tumors. Hypoxia-inducible factors (HIFs) are principle regulators of hypoxic adaptation, regulating gene expression involved in glycolysis, erythropoiesis, angiogenesis, proliferation, and stem cell function under low O-2. Interestingly, increasing evidence accumulated over recent years suggests an additional important regulatory role for HIFs in inflammation. In macrophages, HIFs not only regulate glycolytic energy generation, but also optimize innate immunity, control pro-inflammatory gene expression, mediate bacterial killing and influence cell migration. In neutrophils, HIF-1 alpha promotes survival under O-2-deprived conditions and mediates blood vessel extravasation by modulating beta(2) integrin expression. Additionally, HIFs contribute to inflammatory functions in various other components of innate immunity, such as dendritic cells, mast cells, and epithelial cells. This review will dissect the role of each HIF isoform in myeloid cell function and discuss their impact on acute and chronic inflammatory disorders. Currently, intensive studies are being conducted to illustrate the connection between inflammation and tumorigenesis. Detailed investigation revealing interaction between microenvironmental factors such as hypoxia and immune cells is needed. We will also discuss how hypoxia and HIFs control properties of tumor-associated macrophages and their relationship to tumor formation and progression.