Interdependence of hypoxic and innate immune responses

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Abstract
Hypoxia-inducible factor (HIF) is a heterodimeric transcription factor regulated at the protein level by oxygen and iron. Under normoxic conditions HIF is degraded, but under hypoxic conditions or iron restriction HIF is stabilized and can bind specific promoters to drive the expression of genes that are involved in glycolysis, angiogenesis and other adaptive programmes for surviving in conditions of hypoxic stress. Increased expression of HIF is observed in cells and tissues in response to infection with diverse infectious microorganisms. Infectious and necrotic tissue foci are themselves hypoxic or anoxic microenvironments. Conditional gene targeting strategies have now revealed that HIF controls various innate immune response genes and cellular processes that aid in pathogen clearance. These include chemotaxis, phagocytosis, antimicrobial peptide production, granule protease release, nitric oxide production and generation of pro-inflammatory cytokines. HIF innate immune activities are evident not only in phagocytic cells such as macrophages and neutrophils but also in dendritic cells, mast cells and epithelial cells with important host defence functions. Analysis of the mechanisms of HIF activation has revealed links between the ancient stress responses of innate immunity and hypoxic adaptation, as nuclear factor-κB controls HIF1α expression at the transcriptional level. Because of its rapid turnover and well-understood mechanism of post-translational stabilization, HIF is a pharmacologically tractable target for enhancing innate immune defence.

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