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Interdependence of hypoxic and innate immune responses

Nature Reviews Immunology volume 9, pages 609–617 (2009)Cite this article

Key Points

  • Hypoxia-inducible factor (HIF) is a heterodimeric transcription factor regulated at the protein level by oxygen and iron. Under normoxic conditions HIF is degraded, but under hypoxic conditions or iron restriction HIF is stabilized and can bind specific promoters to drive the expression of genes that are involved in glycolysis, angiogenesis and other adaptive programmes for surviving in conditions of hypoxic stress.

  • Increased expression of HIF is observed in cells and tissues in response to infection with diverse infectious microorganisms. Infectious and necrotic tissue foci are themselves hypoxic or anoxic microenvironments.

  • Conditional gene targeting strategies have now revealed that HIF controls various innate immune response genes and cellular processes that aid in pathogen clearance. These include chemotaxis, phagocytosis, antimicrobial peptide production, granule protease release, nitric oxide production and generation of pro-inflammatory cytokines.

  • HIF innate immune activities are evident not only in phagocytic cells such as macrophages and neutrophils but also in dendritic cells, mast cells and epithelial cells with important host defence functions.

  • Analysis of the mechanisms of HIF activation has revealed links between the ancient stress responses of innate immunity and hypoxic adaptation, as nuclear factor-κB controls HIF1α expression at the transcriptional level.

  • Because of its rapid turnover and well-understood mechanism of post-translational stabilization, HIF is a pharmacologically tractable target for enhancing innate immune defence.

Abstract

Hypoxia-inducible factor (HIF) is an important transcriptional regulator of cell metabolism and the adaptation to cellular stress caused by oxygen deficiency (hypoxia). Phagocytic cells have an essential role in innate immune defence against pathogens and this is a battle that takes place mainly in the hypoxic microenvironments of infected tissues. It has now become clear that HIF promotes the bactericidal activities of phagocytic cells and supports the innate immune functions of dendritic cells, mast cells and epithelial cells. In response to microbial pathogens, HIF expression is upregulated through pathways involving the key immune response regulator nuclear factor-κB, highlighting an interdependence of the innate immune and hypoxic responses to infection and tissue damage. In turn, HIF-driven innate immune responses have important consequences for both the pathogen and the host, such that the tissue microenvironment fundamentally influences susceptibility to infectious disease.

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Figure 1: Mechanisms of HIF stabilization.
Figure 2: HIF regulation of phagocyte innate immune functions.

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Acknowledgements

The authors' studies in the area of HIF and innate immunity have been supported by US National Institutes of Health grant AI060840 and the American Asthma Foundation.

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  1. Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA. vnizet@ucsd.edu; rsjohnson@ucsd.edu

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    Victor Nizet & Randall S. Johnson

  2. Skaggs School of Pharmacy and Pharmaceutical Sciences, 9500 Gilman Drive, La Jolla, 92093, California, USA

    Victor Nizet

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Glossary

Ubiquitin–proteasome pathway

An important proteolytic pathway that involves the tagging of unwanted proteins with ubiquitin, which allows their recognition by the proteasome — a large, multi-component protein-degrading complex.

Cre recombinase

A site-specific recombinase that recognizes and binds specific sites known as LoxP. Two LoxP sites recombine in the presence of Cre, allowing DNA that is cloned between two such sites to be removed by Cre-mediated recombination.

Cathelicidins

Mammalian cationic microbicidal peptides expressed by epithelial cells and phagocytes that share a highly conserved 'cathelin' 12 kDa pro-sequence at the amino terminus, followed by diversified mature sequences at the carboxyl terminus. Activation of most cathelicidin precursors requires proteolytic cleavage to release the C-terminal domain, which has microbicidal and immunomodulatory activities.

Ischaemia–reperfusion injury

An injury in which the tissue first suffers from hypoxia as a result of severely decreased, or completely arrested, blood flow. Restoration of normal blood flow then triggers inflammation, which exacerbates the tissue damage.

Caecal ligation and puncture

An experimental model of peritonitis in rodents, in which the caecum is ligated and then punctured. This leads to leakage of intestinal bacteria into the peritoneal cavity and subsequent peritoneal infection.

Siderophores

Low-molecular-mass compounds that are secreted by numerous types of bacteria and that have a high affinity for iron and other metal ions. These molecules chelate metal ions and carry them into the cell through specific receptors, promoting bacterial survival in the host.

Z-DNA-forming microsatellite polymorphisms

Microsatellites such as the SLC11A1 (GT/CA)n dinucleotide repeat tend to form Z-DNA, an unstable left-handed form of DNA that is transiently induced during gene transcription by a moving RNA polymerase and stabilized by negative supercoiling. Polymorphisms in such microsatellites can activate or repress gene transcription in a context-dependent manner.

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Nizet, V., Johnson, R. Interdependence of hypoxic and innate immune responses. Nat Rev Immunol 9, 609–617 (2009). https://doi.org/10.1038/nri2607

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