The effect of HIF on metabolism and immunity

Hypoxia-dependent changes in cellular metabolism have important implications for the effective functioning of multiple immune cell subtypes. This Review describes the inputs that shape the hypoxic response in individual cell types and contexts, and the implications of this response for cellular metabolism and associated alterations in immune cell function. Cellular hypoxia occurs when the demand for sufficient molecular oxygen needed to produce the levels of ATP required to perform physiological functions exceeds the vascular supply, thereby leading to a state of oxygen depletion with the associated risk of bioenergetic crisis. To protect against the threat of hypoxia, eukaryotic cells have evolved the capacity to elicit oxygen-sensitive adaptive transcriptional responses driven primarily (although not exclusively) by the hypoxia-inducible factor (HIF) pathway. In addition to the canonical regulation of HIF by oxygen-dependent hydroxylases, multiple other input signals, including gasotransmitters, non-coding RNAs, histone modifiers and post-translational modifications, modulate the nature of the HIF response in discreet cell types and contexts. Activation of HIF induces various effector pathways that mitigate the effects of hypoxia, including metabolic reprogramming and the production of erythropoietin. Drugs that target the HIF pathway to induce erythropoietin production are now approved for the treatment of chronic kidney disease-related anaemia. However, HIF-dependent changes in cell metabolism also have profound implications for functional responses in innate and adaptive immune cells, and thereby heavily influence immunity and the inflammatory response. Preclinical studies indicate a potential use of HIF therapeutics to treat inflammatory diseases, such as inflammatory bowel disease. Understanding the links between HIF, cellular metabolism and immunity is key to unlocking the full therapeutic potential of drugs that target the HIF pathway.

Automated summary

Hypoxia-induced changes in cellular metabolism and immune cell function are regulated by the HIF pathway. Understanding the links between HIF, cellular metabolism, and immunity is crucial for developing effective therapeutic strategies.