Oxygen Sensing in Innate Immune Cells: How Inflammation Broadens Classical Hypoxia-Inducible Factor Regulation in Myeloid Cells

Significance: Oxygen deprivation (hypoxia) is a common feature at sites of inflammation. Immune cells and all other cells present at the inflamed site have to adapt to these conditions. They do so by stabilization and activation of hypoxia-inducible factor subunit α (HIF-1α and HIF-2α, respectively), enabling constant generation of adenosine triphosphate (ATP) under these austere conditions by the induction of, for example, glycolytic pathways. Recent Advances: During recent years, it has become evident that HIFs play a far more important role than initially believed because they shape the inflammatory phenotype of immune cells. They are indispensable for migration, phagocytosis, and the induction of inflammatory cytokines by innate immune cells and thereby enable a crosstalk between innate and adaptive immunity. In short, they ensure the survival and function of immune cells under critical conditions. Critical Issues: Up to now, there are still open questions regarding the individual roles of HIF-1 and HIF-2 for the different cell types. In particular, the loss of both HIF-1 and HIF-2 in myeloid cells led to unexpected and contradictory results in the mouse models analyzed so far. Similarly, the role of HIF-1 in dendritic cell maturation is unclear due to inconsistent results from in vitro experiments. Future Directions: The HIFs are indispensable for immune cell survival and action under inflammatory conditions, but they might also trigger over-activation of immune cells. Therefore, they might be excellent setscrews to adjust the inflammatory response by pharmaceuticals. China and Japan and very recently (August 2021) Europe have approved prolyl hydroxylase inhibitors (PHIs) to stabilize HIF such as roxadustat for clinical use to treat anemia by increasing the production of erythropoietin, the classical HIF target gene. Nonetheless, we need further work regarding the use of PHIs under inflammatory conditions, because HIFs show specific activation and distinct expression patterns in innate immune cells. The extent to which HIF-1 or HIF-2 as a transcription factor regulates the adaptation of immune cells to inflammatory hypoxia differs not only by the cell type but also with the inflammatory challenge and the surrounding tissue. Therefore, we urgently need isoform- and cell type-specific modulators of the HIF pathway. Antioxid. Redox Signal. 37, 956-971.