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Regulation of immunity and inflammation by hypoxia in immunological niches

Nature Reviews Immunology volume 17, pages 774–785 (2017)Cite this article

Subjects

Key Points

  • Hypoxia and inflammation are frequently co-incidental microenvironmental features of sites of concentrated physiological or pathological immune activity.

  • Hypoxia activates hypoxia-inducible factor, which is a major regulator of multiple aspects of immune cell function. Consequently, hypoxia plays a key role in the regulation of immunity and inflammation.

  • The impact of hypoxia on immunity and inflammation is site-specific and cell type-specific.

  • Pharmacological hydroxylase inhibition, which activates hypoxia-sensitive pathways, is profoundly protective in multiple models of inflammation.

Abstract

Immunological niches are focal sites of immune activity that can have varying microenvironmental features. Hypoxia is a feature of physiological and pathological immunological niches. The impact of hypoxia on immunity and inflammation can vary depending on the microenvironment and immune processes occurring in a given niche. In physiological immunological niches, such as the bone marrow, lymphoid tissue, placenta and intestinal mucosa, physiological hypoxia controls innate and adaptive immunity by modulating immune cell proliferation, development and effector function, largely via transcriptional changes driven by hypoxia-inducible factor (HIF). By contrast, in pathological immunological niches, such as tumours and chronically inflamed, infected or ischaemic tissues, pathological hypoxia can drive tissue dysfunction and disease development through immune cell dysregulation. Here, we differentiate between the effects of physiological and pathological hypoxia on immune cells and the consequences for immunity and inflammation in different immunological niches. Furthermore, we discuss the possibility of targeting hypoxia-sensitive pathways in immune cells for the treatment of inflammatory disease.

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Figure 1: Hypoxia in physiological immunological niches.
Figure 2: Hypoxia in pathological immunological niches.
Figure 3: The HIF pathway.

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Acknowledgements

Work from the authors' laboratories is funded through research grants from Science Foundation Ireland, the European Union and the US National Institutes of Health.

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Authors and Affiliations

  1. UCD Conway Institute, Systems Biology Ireland and the School of Medicine, University College Dublin, Belfield, 4, Dublin, Ireland

    Cormac T. Taylor

  2. Department of Medicine and the Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, 80045, Colorado, USA

    Sean P. Colgan

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C.T.T. and S.P.C. both contributed to discussions of the content and the writing, review and editing of this manuscript

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Correspondence to Cormac T. Taylor.

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C.T.T. and S.P.C. are members of the Scientific Advisory Board of Akebia Therapeutics.

PowerPoint slides

Glossary

Microenvironmental features

Physiochemical conditions found within a specific niche or tissue.

Hypoxia

The condition that arises when cellular oxygen demand exceeds supply.

Electron transport chain

(ETC). Primary eukaryotic system for the reduction of molecular oxygen and the generation of ATP. Located within mitochondria.

Oxidative phosphorylation

(OXPHOS). The generation of cellular ATP using energy derived from electron transport during aerobic respiration.

Lysosomal degradation pathway

A mechanism of intracellular protein degradation that involves proteolysis in lysosomal compartments.

Glycolysis

The utilization of glucose to generate ATP.

Physiological angiogenesis

The normal growth of blood vessels in healthy tissues.

Carotid body

Small organelle situated at the bifurcation of the carotid artery responsible for sensing blood oxygen levels and regulating the respiratory rate.

Semi-allogeneic trophoblasts

Fetal cells that express both maternal and paternal surface antigens.

Crypt–villus axis

Structure at the mucosal surface of the small intestine.

Erythropoiesis

The process by which red blood cell production is controlled. Involves the release of erythropoietin from cells of the kidney and liver.

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Taylor, C., Colgan, S. Regulation of immunity and inflammation by hypoxia in immunological niches. Nat Rev Immunol 17, 774–785 (2017). https://doi.org/10.1038/nri.2017.103

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