If it’s not one thing, HIF’s another: immunoregulation by hypoxia inducible factors in disease

Hammond, Ffion R; Lewis, Amy; Elks, Philip M.

doi:10.1111/febs.15476

Cited by 15 publications

(14 citation statements)

References 82 publications

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“…Instead, we focus on a physiological role for HIF and its metabolic effects in rapidly dividing cells of the immune system during immune and inflammatory responses. The diverse roles of HIF in the control of immune cell function have been covered elsewhere 5 , 153 – 156 , and so here we focus on more recent findings — mainly from the past few years — on the role of HIF in regulating immune cell phenotype and function, and the physiological consequences of these effects for infection and inflammation.…”

Section: Implications Of Hif-mediated Changes In Cell Metabolismmentioning

confidence: 99%

The effect of HIF on metabolism and immunity

2022

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Cellular hypoxia occurs when the demand for sufficient molecular oxygen needed to produce the levels of ATP required to perform physiological functions exceeds the vascular supply, thereby leading to a state of oxygen depletion with the associated risk of bioenergetic crisis. To protect against the threat of hypoxia, eukaryotic cells have evolved the capacity to elicit oxygen-sensitive adaptive transcriptional responses driven primarily (although not exclusively) by the hypoxia-inducible factor (HIF) pathway. In addition to the canonical regulation of HIF by oxygen-dependent hydroxylases, multiple other input signals, including gasotransmitters, non-coding RNAs, histone modifiers and post-translational modifications, modulate the nature of the HIF response in discreet cell types and contexts. Activation of HIF induces various effector pathways that mitigate the effects of hypoxia, including metabolic reprogramming and the production of erythropoietin. Drugs that target the HIF pathway to induce erythropoietin production are now approved for the treatment of chronic kidney disease-related anaemia. However, HIF-dependent changes in cell metabolism also have profound implications for functional responses in innate and adaptive immune cells, and thereby heavily influence immunity and the inflammatory response. Preclinical studies indicate a potential use of HIF therapeutics to treat inflammatory diseases, such as inflammatory bowel disease. Understanding the links between HIF, cellular metabolism and immunity is key to unlocking the full therapeutic potential of drugs that target the HIF pathway.

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Section: Implications Of Hif-mediated Changes In Cell Metabolismmentioning

confidence: 99%

The effect of HIF on metabolism and immunity

2022

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“…In contrast, when oxygen is limited, these HIFα subunits translocate to the nucleus, dimerize with HIF-1β and regulate the transcription of host genes involved in cell metabolism and immune regulation. 12 The majority of reports studying HBV replication in vitro are performed at atmospheric oxygen levels (18%) where HIFs are inactive, so their role in viral replication has been overlooked. We evaluated the effect of HIF signaling on HBV replication and uncovered a positive role for HIFs in activating viral transcription that could inform future therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia inducible factors regulate hepatitis B virus replication by activating the basal core promoter

Wing

Liu

Harris

et al. 2021

Journal of Hepatology

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…Thus, not all HIF-1 activation can be considered harmful and the therapeutic inhibition of this pathway must be balanced against its beneficial contribution. Nonetheless, targeting the HIF signaling pathway in chronic respiratory disease may still hold promise in effectively managing or delaying the progression of disease ( 203 ). Novel therapeutics could be developed which specifically interfere with mRNA expression, protein synthesis, protein degradation, protein dimerization, DNA binding or transcriptional activity of HIF-1.…”

Section: Discussionmentioning

confidence: 99%

Influence of Hypoxia on the Epithelial-Pathogen Interactions in the Lung: Implications for Respiratory Disease

et al. 2021

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Under normal physiological conditions, the lung remains an oxygen rich environment. However, prominent regions of hypoxia are a common feature of infected and inflamed tissues and many chronic inflammatory respiratory diseases are associated with mucosal and systemic hypoxia. The airway epithelium represents a key interface with the external environment and is the first line of defense against potentially harmful agents including respiratory pathogens. The protective arsenal of the airway epithelium is provided in the form of physical barriers, and the production of an array of antimicrobial host defense molecules, proinflammatory cytokines and chemokines, in response to activation by receptors. Dysregulation of the airway epithelial innate immune response is associated with a compromised immunity and chronic inflammation of the lung. An increasing body of evidence indicates a distinct role for hypoxia in the dysfunction of the airway epithelium and in the responses of both innate immunity and of respiratory pathogens. Here we review the current evidence around the role of tissue hypoxia in modulating the host-pathogen interaction at the airway epithelium. Furthermore, we highlight the work needed to delineate the role of tissue hypoxia in the pathophysiology of chronic inflammatory lung diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease in addition to novel respiratory diseases such as COVID-19. Elucidating the molecular mechanisms underlying the epithelial-pathogen interactions in the setting of hypoxia will enable better understanding of persistent infections and complex disease processes in chronic inflammatory lung diseases and may aid the identification of novel therapeutic targets and strategies.

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If it’s not one thing, HIF’s another: immunoregulation by hypoxia inducible factors in disease

Cited by 15 publications

References 82 publications

The effect of HIF on metabolism and immunity

The effect of HIF on metabolism and immunity

Hypoxia inducible factors regulate hepatitis B virus replication by activating the basal core promoter

Influence of Hypoxia on the Epithelial-Pathogen Interactions in the Lung: Implications for Respiratory Disease

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