Abstract
Hypoxia describes limited oxygen availability at the cellular level. Myeloid cells are exposed to hypoxia at various bodily sites and even contribute to hypoxia by consuming large amounts of oxygen during respiratory burst. Hypoxia-inducible factors (HIFs) are ubiquitously expressed heterodimeric transcription factors, composed of an oxygen-dependent α and a constitutive β subunit. The stability of HIF-1α and HIF-2α is regulated by oxygen-sensing prolyl-hydroxylases (PHD). HIF-1αand HIF-2α modify the innate immune response and are context dependent. We provide a historic perspective of HIF discovery, discuss the molecular components of the HIF pathway, and how HIF-dependent mechanisms modify myeloid cell functions. HIFs enable myeloid-cell adaptation to hypoxia by up-regulating anaerobic glycolysis. In addition to effects on metabolism, HIFs control chemotaxis, phagocytosis, degranulation, oxidative burst, and apoptosis. HIF-1α enables efficient infection defense by myeloid cells. HIF-2αdelays inflammation resolution and decreases antitumor effects by promoting tumor-associated myeloid-cell hibernation. PHDs not only control HIF degradation, but also regulate the crosstalk between innate and adaptive immune cells thereby suppressing autoimmunity. HIF-modifying pharmacologic compounds are entering clinical practice. Current indications include renal anemia and certain cancers. Beneficial and adverse effects on myeloid cells should be considered and could possibly lead to drug repurposing for inflammatory disorders.
Highlights
Myeloid cells consist of granulocytes, mostly neutrophils, and monocytes
We provide a historic perspective of Hypoxia-inducible factor (HIF) discovery, discuss the molecular components of the HIF pathway, and how HIF-dependent mechanisms modify myeloid cell functions
CREB-binding protein (CBP) and p300 bind to HIFα/β heterodimers with nonhydroxylated asparagine residues in the C terminal transactivation domain (C-TAD).[101,103,104]
Summary
Myeloid cells consist of granulocytes, mostly neutrophils, and monocytes. Once released from the bone marrow, these cells circulate in the blood and are recruited to inflammatory sites where they execute functions that protect the host from infectious and noninfectious challenges. Hypoxia describes low oxygen availability at the tissue level that is further categorized into hypoxemic, anemic, circulatory, and histotoxic hypoxia.[1] During their life span, myeloid cells encounter a wide range of oxygen partial pressures. Gradient with >70 mm Hg in the cortex and 10 mm Hg in the medulla.[4] Importantly, hypoxia is characteristic of inflamed tissues,[5,6] where activated myeloid cells migrate against a low oxygen supply.[7]. Mitochondrial oxidative phosphorylation is strongly decreased, and most ATP is provided by the conversion of pyruvate into lactate.[7] Hypoxia-inducible factors (HIFs) are ubiquitous transcriptional regulators of gene expression in response to low oxygen availability. HIFs help myeloid cells to cope with low oxygen conditions by modifying several metabolic and inflammatory aspects. We discuss the HIF system with its implications for myeloid cell functions together with the potential effects of HIF-directed treatments
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