Journal
JOURNAL OF LEUKOCYTE BIOLOGY
Volume 110, Issue 1, Pages 61-75Publisher
OXFORD UNIV PRESS
DOI: 10.1002/JLB.4RI0820-535R
Keywords
hypoxia-inducible factor; hypoxia; innate immunity; myeloid cells
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Funding
- Deutsche Forschungsgemeinschaft (DFG) [394046635-SFB 1365]
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Hypoxia affects myeloid cells, while HIFs play a crucial role in modulating myeloid cell functions to adapt to low oxygen environments. HIF-1α and HIF-2α are key players in the innate immune response, though with different impact mechanisms.
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 alpha and a constitutive beta subunit. The stability of HIF-1 alpha and HIF-2 alpha is regulated by oxygen-sensing prolyl-hydroxylases (PHD). HIF-1 alpha and HIF-2 alpha 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-1 alpha enables efficient infection defense by myeloid cells. HIF-2 alpha delays 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.
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