Hypoxia. Hypoxia, hypoxia inducible factor and myeloid cell function

Sarah R Walmsley,Moira Kb Whyte,Edwin R Chilvers

doi:10.1186/ar2632

Abstract

With little in the way of effective therapeutic strategies to target the innate immune response, a better understanding of the critical pathways regulating neutrophil and macrophage responses in inflammation is key to the development of novel therapies. Hypoxia inducible factor (HIF) was originally identified as a central transcriptional regulator of cellular responses to oxygen deprivation. However, the HIF signalling pathway now appears, in myeloid cells at least, to be a master regulator of both immune cell function and survival. As such, understanding the biology of HIF and its regulators may provide new approaches to myeloid-specific therapies that are urgently needed.

Highlights

Despite the evolution of respiratory and cardiovascular systems in multicellular higher organisms, the presence of physiological oxygen gradients within and across tissues is well described
It makes sense that myeloid cells have adapted to function at these sites of relative tissue hypoxia, subversion of this response may be important in the persistent inflammation associated with inflammatory arthritides, notably rheumatoid arthritis where tissue hypoxia is linked to disease severity and progression
Given the profound survival effect of hypoxia on neutrophils aged in vitro [11,12], and the critical role for Hypoxia inducible factor (HIF) in regulating cellular responses to hypoxia, we studied the importance of HIF itself in regulating neutrophil apoptosis

Summary

Introduction

Despite the evolution of respiratory and cardiovascular systems in multicellular higher organisms, the presence of physiological oxygen gradients within and across tissues is well described. HIF-1α has been shown, to promote the expression of NF-κB-regulated inflammatory cytokines [40], and loss of HIF-1α results in the downregulation of hypoxia-induced NF-κB message in murine bone-marrow-derived neutrophils [45] Whilst these data clearly highlight crosstalk between the HIF and NF-κB pathways, the consequences of these associations both in vitro and in vivo and the variation between the cell types studied makes functional interpretation of these existing data difficult. Its role in inflammatory iron sequestration is somewhat controversial given the reported post-transcriptional downregulation of TfR1 following prolonged in vitro exposure of macrophages (10 to 24 hours) to bacterial lipopolysaccharide IFNγ [55] Work by this group and others, describes an initial early induction of TfR1 (30 min) that involves the successive activation of NF-κB and HIF-1 signalling pathways [53]. This would make HIF the true master regulator of innate immune myeloid cell-mediated responses

Conclusions

Findings

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