Regulation of immunity and inflammation by hypoxia in immunological niches

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. Access through your

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OXYGENATION SHAPES IMMUNE RESPONSES: EMERGING ROLES FOR PHYSIOXIA AND PATHOLOGICAL HYPOXIA Article 30 September 2024 THE EFFECT OF HIF ON METABOLISM AND IMMUNITY Article 20 June 2022 HYPOXIA

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G1076–G1090 (2016). Article  PubMed  Google Scholar  Download references 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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * UCD Conway Institute, Systems Biology Ireland and the School of Medicine,

University College Dublin, Belfield, 4, Dublin, Ireland Cormac T. Taylor * Department of Medicine and the Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora,

80045, Colorado, USA Sean P. Colgan Authors * Cormac T. Taylor View author publications You can also search for this author inPubMed Google Scholar * Sean P. Colgan View author publications

You can also search for this author inPubMed Google Scholar CONTRIBUTIONS C.T.T. and S.P.C. both contributed to discussions of the content and the writing, review and editing of this

manuscript CORRESPONDING AUTHOR Correspondence to Cormac T. Taylor. ETHICS DECLARATIONS COMPETING INTERESTS C.T.T. and S.P.C. are members of the Scientific Advisory Board of Akebia

Therapeutics. POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR FIG. 3 POWERPOINT SLIDE FOR TABLE 1 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. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation *

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