Abstract
Hypoxia‐inducible factors (HIFs) have emerged in recent years as critical regulators of immunity. Localised, low oxygen tension is a hallmark of inflamed and infected tissues. Subsequent myeloid cell HIF stabilisation plays key roles in the innate immune response, alongside emerging oxygen‐independent roles. Manipulation of regulatory proteins of the HIF transcription factor family can profoundly influence inflammatory profiles, innate immune cell function and pathogen clearance and, as such, has been proposed as a therapeutic strategy against inflammatory diseases. The direction and mode of HIF manipulation as a therapy are dictated by the inflammatory properties of the disease in question, with innate immune cell HIF reduction being, in general, advantageous during chronic inflammatory conditions, while upregulation of HIF is beneficial during infections. The therapeutic potential of targeting myeloid HIFs, both genetically and pharmacologically, has been recently illuminated in vitro and in vivo, with an emerging range of inhibitory and activating strategies becoming available. This review focuses on cutting edge findings that uncover the roles of myeloid cell HIF signalling on immunoregulation in the contexts of inflammation and infection and explores future directions of potential therapeutic strategies.
Highlights
Hypoxia-inducible factors (HIFs) are master transcriptional regulators of the cellular response to hypoxia, that have influential roles in innate immune cell behaviour during inflammation and infections [1]
HIF stabilisation in normoxia has been shown to increase neutrophil neutrophil extracellular trap (NET) formation through mammalian target of rapamycin [19]
Macrophages are a key cellular component of innate immunity, and like neutrophils, their function, migration and behaviours are influenced by hypoxia and HIF signalling [20]
Summary
Hypoxia-inducible factors (HIFs) are master transcriptional regulators of the cellular response to hypoxia, that have influential roles in innate immune cell behaviour during inflammation and infections [1]. HIF stabilisation in normoxia has been shown to increase neutrophil NET formation through mammalian target of rapamycin (mTOR) [19] These observations could be especially important in understanding later stage COVID-19 infection, where NET formation is predicted to play a major role in lung physiology [18]. Macrophages are a key cellular component of innate immunity, and like neutrophils, their function, migration and behaviours are influenced by hypoxia and HIF signalling [20]. Treatment of HIF-a inhibitor YC-1, in a mouse injury model, decreased numbers of pro-inflammatory macrophages in scar tissue and reduced levels of proinflammatory cytokines in vivo [30]. These studies indicate that macrophage HIF-targeted therapies could allow a return to tissue homoeostasis after injury/inflammation
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