Hypoxia-inducible factors: key regulators of myeloid cells during inflammation
Nan Lin, M. Celeste Simon
Nan Lin, M. Celeste Simon
Published October 3, 2016; First published September 6, 2016
Citation Information: J Clin Invest. 2016;126(10):3661-3671. https://doi.org/10.1172/JCI84426.
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Category: Review Series

Hypoxia-inducible factors: key regulators of myeloid cells during inflammation

Abstract

Hypoxia is a prominent characteristic of many acute or chronic inflammatory diseases, and exerts significant influence on their progression. Macrophages and neutrophils are major cellular components of innate immunity and contribute not only to O2 deprivation at the site of inflammation, but also alter many of their functions in response to hypoxia to either facilitate or suppress inflammation. Hypoxia stabilizes HIF-αs in macrophages and neutrophils, and these O2-sensitive transcription factors are key regulators of inflammatory responses in myeloid cells. In this review, we will summarize our current understanding of the role of HIF-αs in shaping macrophage and neutrophil functions in the pathogenesis and progression of multiple inflammatory diseases.

Authors

Nan Lin, M. Celeste Simon

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Figure 1

Overview of the roles of HIF-1α and HIF-2α in myeloid cells.

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Overview of the roles of HIF-1α and HIF-2α in myeloid cells. Both HIF-1α...
Both HIF-1α and HIF-2α are required for key macrophage functions, such as cytokine production and the ability to migrate and invade. However, macrophage glycolysis, ATP generation, and bactericidal activity have been related to HIF-1α exclusively. Nevertheless, both isoforms contribute to pathogenesis of various acute inflammatory syndromes. Additionally, the roles of myeloid HIF-αs in the setting of tumor inflammation are currently being investigated. As compared with macrophages, less is known about HIF-αs in neutrophils. However, it is very clear that both isoforms are required to inhibit neutrophil apoptosis and elongate their lifespan. While HIF-1α facilitates bacterial killing by neutrophils, many neutrophil functions seem less dependent on HIF-2α, including respiratory burst, chemotaxis, and phagocytosis. Nevertheless, increased neutrophil HIF-2α accumulation correlates with increased neutrophilic inflammation and lung injury in an LPS-induced acute lung injury murine model.