Interdependence of hypoxic and innate immune responses

Abstract

Hypoxia-inducible factor (HIF) is an important transcriptional regulator of cell metabolism and the adaptation to cellular stress caused by oxygen deficiency (hypoxia). Phagocytic cells have an essential role in innate immune defence against pathogens and this is a battle that takes place mainly in the hypoxic microenvironments of infected tissues. It has now become clear that HIF promotes the bactericidal activities of phagocytic cells and supports the innate immune functions of dendritic cells, mast cells and epithelial cells. In response to microbial pathogens, HIF expression is upregulated through pathways involving the key immune response regulator nuclear factor-kappaB, highlighting an interdependence of the innate immune and hypoxic responses to infection and tissue damage. In turn, HIF-driven innate immune responses have important consequences for both the pathogen and the host, such that the tissue microenvironment fundamentally influences susceptibility to infectious disease.

Figure 1. Mechanisms of HIF stabilization

The current picture of post-translational regulation of the HIF response: Under normoxic conditions, hydroxylation by prolyl hydroxylases in an O2-dependent manner at the aa residues 402 and 564 acts to allow recognition/binding of HIF by the VHL complex which assembles in a classical SCF-like fashion around cullin-2, elongins B and C, and other elements of ubiquitination machinery. This results in a polyubiquitination of the HIF protein and its ultimate destruction by proteasomes. The asparagine hydroxylase FIH acts more or less in concert with the prolyl hydroxylation, although in this case to hydroxylate an asparagine residue in the C-terminal domain of HIF. This acts to block association with the p300/CBP protein; this in turn inhibits transcriptional enhancement by the HIF complex. As all of these post-translational events are dependent on intracellular oxygen, they are inhibited by hypoxia, and thus activation and transcription of HIF target genes facilitated when the various hydroxylations fail to occur, as depicted on the right.

Figure 2. HIF regulation of phagocyte innate immune functions

Myeloid-derived phagocytes such as neutrophils and macrophages have low hypoxia-inducible factor (HIF) levels at baseline as they circulate in the oxygen-rich blood. When recruited to tissue sites of infection, they migrate across the endothelium and immediately encounter a decreasing oxygen gradient, which leads to reduced prolyl hydroxylase activity and increased stabilization of HIF1α protein, which translocates to the nucleus and forms a functional heterodimeric transcription factor with HIF1β. Expression of innate immune response genes that contain hypoxia-responsive elements (HREs) in their promoters is increased, but maximal activation occurs only through Toll-like receptors (TLRs) and nuclear factor-KB (NF-κB) activation following pathogen encounter, which functions to boost HIF1α transcription. HIF activity promotes phagocytosis, inhibits apoptosis to increase phagocyte lifespan, stimulates the release of antimicrobial peptides, granule proteases, and pro-inflammatory cytokines such as tumour necrosis factor (TNF), interleukin-1 (IL-1) and IL-12, upregulates TLR expression, and activates the production of nitric oxide (NO) via inducible NO synthase (iNOS). NO interferes with HIF degradation, thereby creating an amplification loop for rapid phagocyte activation.