Targeting the HIF pathway in inflammation and immunity.

Oxygen deprivation (hypoxia) is a frequently encountered condition in both health and disease. Metazoans have evolved an elegant and direct cellular mechanism by which to sense local oxygen levels and mount an adaptive transcriptional response to hypoxia which is mediated by a transcription factor termed the hypoxia-inducible factor (HIF). In normoxia, HIF is repressed primarily through the action of a family of hydroxylases, which target HIFα subunits for degradation in an oxygen-dependent manner. In hypoxia, HIF is rapidly stabilized in cells thus allowing it to regulate the expression of hundreds of genes which promote an adaptive response including genes expressing regulators of angiogenesis, metabolism, growth and survival. Initial studies into the HIF pathway focused mainly on its role in supporting tumor adaptation through enhancing processes such as angiogenesis, glycolytic metabolism and cell survival. More recently however, it has become clear that the HIF pathway also plays a key role in the regulation of immunity and inflammation. In fact, conditional knockout of the HIF-1α subunit has identified key immune roles in T-cells, dendritic cells, macrophages, neutrophils and epithelial cells. In this review, we will consider the role for HIF in the regulation of the immune response and its possible contribution to inflammation. Furthermore, we will consider potential therapeutic strategies, which target the HIF pathway in chronic inflammatory and infectious disease.