Hypoxia‐inducible factors in metabolic reprogramming during sepsis

Sepsis is a highly heterogeneous syndrome that is caused by an imbalanced host response to infection. Despite huge investments, sepsis remains a contemporary threat with significant burden on health systems. Vascular dysfunction and elevated oxygen consumption by highly metabolically active immune cells result in tissue hypoxia during inflammation. The transcription factor hypoxia‐inducible factor‐1a (HIF1α), and its family members, plays an important role in cellular metabolism and adaptation to cellular stress caused by hypoxia. In this review, we discuss the role of HIF in sepsis. We show possible mechanisms by which the inflammatory response activated during sepsis affects the HIF pathway. The activated HIF pathway in turn changes the metabolism of both innate and adaptive immune cells. As HIF expression in leukocytes of septic patients can be directly linked with mortality, we discuss multiple ways of interfering with the HIF signaling pathway. Inflammation creates a hypoxic response resulting from decreased oxygen delivery and increased oxygen consumption. Hypoxia‐inducible factor (HIF) can be activated before hypoxia appears. By limiting iron or succinate availability, inflammation can lead to HIF accumulation in normoxic condition. HIF1α drives expression of regulating erythropoetese (EPO1) and regulating angiogenesis (VEGF) counteracting the hypoxic response. Next, HIF1α drives transcription of a number of rate‐limiting enzymes, which increases glycolysis and promotes immune cell function.