Hypoxia HIF and Inflammation Cellular responses to hypoxia a
Hypoxia, HIF, and Inflammation
Cellular responses to hypoxia are essential for life and are now recognized to be dysregulated in a wide range of disease processes. The key players in these pathways are a family of transcription factors, the hypoxia-inducible factors (HIFs; see Glossary), as well as their regulatory proteins, the prolyl hydroxylase domain enzymes (PHDs) and factor inhibiting HIF (FIH, also known as HIF1α subunit inhibitor, HIF1AN) (Figure 1).
The PHDs are also termed EGLNs owing to their early identification as homologs of the C. elegans oxygen sensor EGL-nine. In this nomenclature PHD1 is termed EGLN2, PHD2 is termed EGLN1, and PHD3 is known as EGLN3. There are multiple links between hypoxia signaling pathways and inflammatory processes. Inflammation may lead to local or systemic hypoxia, for example in an abscess where lack of blood supply results in profound local hypoxia, or in acute lung inflammation (such as acute respiratory distress syndrome, ARDS) where impaired gas exchange can lead to systemic hypoxia. In addition, an influx of inflammatory RI-1 may lead to hypoxia because the demand for oxygen outstrips supply, so-called inflammatory hypoxia . The links between hypoxia signaling and inflammation are bidirectional: hypoxia may also exacerbate inflammation through activation of inflammatory pathways and effects on immune cell fate and function. The HIF/PHD pathway can also be activated in normoxia in response to inflammatory stimuli. For example, lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) ligand, has been shown to upregulate HIF1α in macrophages , and T cell receptor (TCR) engagement contributes to HIF1α and HIF2α (also known as endothelial PAS domain protein 1, EPAS1) protein accumulation in T cells 3, 4. It is also important to consider that the PHDs have been postulated to have HIF-independent activity in the context of inflammation and malignancy. NF-κB is a transcription factor which, like HIF, regulates a diverse group of genes including cytokines, immune receptors, and stress-response genes . In some contexts NF-κB activity is linked to hypoxia signaling in a HIF-dependent fashion 6, 7. However, there is also evidence that PHD activity may directly regulate NF-κB, impacting on inflammatory and malignant outcomes 8, 9, 10. FIH has also been found to regulate NF-κB activity, and Fih (Hif1an) and Phd1 (Egln2) knockouts had an additive effect in reducing NF-κB activity . Furthermore, PHD activity has been found to have HIF-independent effects on cell proliferation and survival via PHD1-dependent hydroxylation of the tumor-suppressor protein p53  and the transcription factor FOXO3a , as well as via PHD3-mediated regulation of the epidermal growth factor receptor (EGFR) . Thus, crosstalk between inflammation and hypoxia has important implications in infection, sterile inflammation, ischemic injury, and within the tumor microenvironment. The optimum cellular response to hypoxia is highly cell- and context-specific, and can be modulated by multiple environmental cues.
HIF/PHD Isoforms: Overlapping but Distinct Roles Despite similarities in structure and function of HIFα isoforms, there are key differences in the transcriptional repertoires of HIF1α and HIF2α which afford an additional level of complexity in the transcriptional response to hypoxia (reviewed in ). This differentiation is multifactorial, relating to variations in tissue expression, temporal regulation, and gene specificity. Interestingly, this specificity is driven not by the DNA-binding domain but by the N-terminal transactivation domain . The balance of HIF1α versus HIF2α has important implications for inflammation. PHDs 1–3 were identified in 2001 as the oxygen sensors regulating HIF 17, 18. All three mammalian PHD isoforms have HIF hydroxylation activity . The specific function of each HIF and PHD isoform is the subject of extensive and ongoing research. The generation of cell- and isoform-specific knockout mice (often using ) and other techniques such as small interfering RNAs (siRNAs)  have enabled researchers to begin to elucidate the function of specific PHDs. These studies, as well as those utilizing pharmacological inhibition of this pathway, identify diverse and complex roles for individual pathway members in the inflammatory response.