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The HIF/VHL Pathway

From Oxygen Sensing to Innate Immunity

¹ Academic Unit of Respiratory Medicine, School of Medicine and Biomedical Sciences, University of Sheffield, Royal Hallamshire Hospital, Sheffield; and ² Respiratory Medicine Division, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Cambridge, United Kingdom

Correspondence and requests for reprints should be addressed to Professor E. R. Chilvers, Respiratory Medicine Division, Department of Medicine, University of Cambridge School of Clinical Medicine, Box 157, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. E-mail: erc24{at}cam.ac.uk

	Abstract

Top Abstract CLINICAL RELEVANCE OXYGEN AND EUKARYOTES HIF AND OXYGEN SENSING GLYCOLYSIS AND INFLAMMATION NEUTROPHIL APOPTOSIS AND... AN OXYGEN-INDEPENDENT ROLE FOR... DOWNSTREAM HIF-1{alpha}... CONCLUSIONS References

 
In aerobic organisms, all cells have the capacity to respond to changes in oxygenation through the stabilization and transcriptional activation of hypoxia-inducible factor (HIF). At sites of tissue injury, oxygen delivery to individual cells may be compromised or insufficient due to increased metabolic demands, and it is to these areas that immune cells, including neutrophils, must migrate and operate effectively. In addition to the role of HIF to regulate the adaptive metabolic and survival responses of these cells at sites of reduced oxygenation, more complex interactions between HIF and pro-inflammatory pathways are now emerging. The mechanisms by which HIF modulates pro-inflammatory myeloid cell lifespan and function remain to be fully characterized, but roles for the oxygen-sensing hydroxylase enzymes through direct hydroxylation of NF-B and its repressor protein IB have been suggested. The ability of HIF to modulate cellular glucose utilization is also thought to be important, with the maintenance of intracellular ATP pools linked to enhanced myeloid cell aggregation, motility, invasiveness, and bacterial killing. Additional non–hypoxia-mediated routes to up-regulate HIF are also now recognized. In this review we describe the role of HIF in the oxygen-sensing response, and the oxygen-dependent and -independent regulation of myeloid cell function and longevity. Understanding these processes and the role they play in regulating innate immune responses within inflamed sites, both hypoxic and normoxic, may offer new opportunities for therapeutic intervention.

Key Words: hypoxia-inducible factor • oxygen • neutrophils

CLINICAL RELEVANCE Top Abstract CLINICAL RELEVANCE OXYGEN AND EUKARYOTES HIF AND OXYGEN SENSING GLYCOLYSIS AND INFLAMMATION NEUTROPHIL APOPTOSIS AND... AN OXYGEN-INDEPENDENT ROLE FOR... DOWNSTREAM HIF-1{alpha}... CONCLUSIONS References   This review highlights new advances in our understanding of how inflammatory cells sense and respond to changes in oxygen tension and the role played by the ubiquitous transcriptional factor hypoxia-inducible factor.

 

	OXYGEN AND EUKARYOTES

Top Abstract CLINICAL RELEVANCE OXYGEN AND EUKARYOTES HIF AND OXYGEN SENSING GLYCOLYSIS AND INFLAMMATION NEUTROPHIL APOPTOSIS AND... AN OXYGEN-INDEPENDENT ROLE FOR... DOWNSTREAM HIF-1{alpha}... CONCLUSIONS References

 
Aerobic organisms depend on the effective delivery of oxygen to individual cells for the sustainable generation of ATP, which is essential for a wide range of biochemical processes. In multicellular eukaryotes, this has required the parallel evolution of respiratory and circulatory systems to achieve adequate oxygen delivery to individual tissues. It is now apparent, however, that the ability of cells to respond to changes in oxygen tension is key to their effective functioning over a range of pathophysiologic oxygen tensions to which they are exposed in vivo. To this end, an oxygen-sensitive transcription factor, hypoxia-inducible factor (HIF) (1), has been identified, which regulates individual cell responses to hypoxia and whose fundamental importance is shown by cross-species conservation in Caenorhabditis elegans (2, 3), Drosophila melanogaster (4, 5), Danio rerio, and indeed all mammals (6, 7).

	HIF AND OXYGEN SENSING

Top Abstract CLINICAL RELEVANCE OXYGEN AND EUKARYOTES HIF AND OXYGEN SENSING GLYCOLYSIS AND INFLAMMATION NEUTROPHIL APOPTOSIS AND... AN OXYGEN-INDEPENDENT ROLE FOR... DOWNSTREAM HIF-1{alpha}... CONCLUSIONS References

 
HIF is a heterodimeric protein composed of a constitutively expressed and promiscuous β-subunit (aryl hydrocarbon nuclear translocator [ARNT]) and a 120-kD oxygen-sensitive -subunit, which is tightly regulated by enzymatic hydroxylation (8, 9). To date, three HIF- subunits have been identified (HIF-1, HIF-2, and HIF-3) (10–12) with variable tissue expression. All HIF- subunits are subject to regulation in two ways: first, proteasomal degradation following hydroxylation of Pro-402 and Pro-564 residues by prolyl hydroxylase domain–containing enzymes (PHD) 1, 2, and 3 (13, 14); and second, transcriptional inactivation following asparaginyl hydroxylation by factor inhibiting HIF (FIH) (15–17) (see Figure 1). This novel group of hydroxylase enzymes (PHDs and FIH) display an absolute requirement for dioxygen, Fe(II) and 2-oxoglutarate (18, 19), and also have homologs in C. elegans and D. melanogaster. The proteosomal degradation of HIF is dependent on the targeting of prolyl hydroxylated -subunits to the ubiquitin pathway by high-affinity binding to the von Hippel Lindau E3 ubiquitin ligase (VHL) (8, 14, 20). The prolyl hydroxylase enzymes are themselves also regulated by ubiquitination, with PHD1 and PHD3 recently identified as targets for the E3 ubiquitin ligases Siah1a and Siah2 (21). At sites of reduced oxygen tension, therefore, reduced PHD and FIH hydroxylase activity permits stabilization and transcriptional activation of HIF, resulting in the modulation of multiple HIF effector genes, which contain hypoxia response elements (HRE) (12), to facilitate the cellular adaptive responses to hypoxia.

View larger version (24K): [in this window] [in a new window]   Figure 1. Regulation of hypoxia-inducible factor (HIF)- accumulation and transcriptional activity by oxygen. In the presence of oxygen, 2-oxoglutarate, ascorbate, and iron PHD and FIH hydroxylate HIF- resulting in proteosomal degradation and transcriptional inactivation. In the absence of oxygen, HIF- accumulates and modulates HRE-responsive genes. PHD, prolyl hydroxylase domain; FIH, factor inhibiting HIF; OH, hydroxylase domain; HRE, hypoxia-response element.

	GLYCOLYSIS AND INFLAMMATION

Top Abstract CLINICAL RELEVANCE OXYGEN AND EUKARYOTES HIF AND OXYGEN SENSING GLYCOLYSIS AND INFLAMMATION NEUTROPHIL APOPTOSIS AND... AN OXYGEN-INDEPENDENT ROLE FOR... DOWNSTREAM HIF-1{alpha}... CONCLUSIONS References

 
In health, physiologic oxygen tensions vary in a tissue and site specific way between 2 and 12 kPa (25, 26). At sites of tissue damage related, for example, to trauma, infection or persistent and exaggerated inflammation, oxygen delivery to individual cells may be severely compromised (e.g., via physical damage to the vascular bed, capillary leak, or phagocyte plugging) or be insufficient for the increased metabolic demands. Cells of the innate immune response are required not only to migrate to areas of tissue damage, characterized by low levels of oxygen and glucose, but also to function effectively to facilitate the neutralization and clearance of injurious stimuli and aid in the rapid resolution of tissue damage. Any subversion of these inflammatory processes would represent a threat to the host organism as a whole, and dictate that the functional longevity of these cells and their adaptive responses to hypoxia need to be tightly controlled.

Neutrophils and mononuclear cells depend principally on glycolysis rather than oxidative metabolism for ATP generation (27–29). Hence, from an energy supply viewpoint, these cells are well placed to function at sites of tissue injury and low oxygen availability. Key enzymes in these glycolytic pathways are themselves HIF-1 targets including glyceraldehyde-3-phosphate dehydrogenase (30, 31) and triosephosphate isomerase-1 (32). A role for HIF-1 in the regulation of myeloid cell function at sites of hypoxia was thus proposed. Work using myeloid targeted HIF-1 knockout mice subsequently confirmed that HIF-1 indeed regulates glycolysis in neutrophils and mononuclear cells both under normoxic and hypoxic conditions (33). The dramatic reduction in ATP pools in the HIF-1–deficient myeloid cells was accompanied by a profound impairment of myeloid cell aggregation, motility, invasiveness, and bacterial bacterial killing (33, 34). In addition, these animals demonstrated a loss of phorbol 12-myristate 13-acetate (PMA)-induced inflammation and rheumatoid serum-induced cartilage destruction (33, 34). While the inhibition of effective glycolysis and consequent reduction in cellular ATP levels was proposed as the major mechanism for the above phenotype, it has also been suggested that HIF-1–dependent changes in β₂-integrin expression may play a role (35). This latter proposal is based on the observation that hypoxia can induce up-regulation of β₂-integrin expression and increase leukocyte adhesion to activated endothelial cells (35). Taken together, these data provide compelling evidence for an inextricable link between the HIF oxygen-sensing pathway and the regulation of myeloid cell function and acute inflammation.

	NEUTROPHIL APOPTOSIS AND INFLAMMATION

Top Abstract CLINICAL RELEVANCE OXYGEN AND EUKARYOTES HIF AND OXYGEN SENSING GLYCOLYSIS AND INFLAMMATION NEUTROPHIL APOPTOSIS AND... AN OXYGEN-INDEPENDENT ROLE FOR... DOWNSTREAM HIF-1{alpha}... CONCLUSIONS References

 
In 2002, we reported that hypoxia has a profound survival effect on human neutrophils aged in vitro (36). This effect was initially considered counterintuitive given the major pro-apoptotic response of many other cells to hypoxia. The role of the hydroxylase/HIF-1/VHL pathway in the regulation of neutrophil apoptosis at sites of inflammation thus needed to be considered. Preliminary data suggested a direct role for HIF-1 in the regulation of neutrophil apoptosis, since neutrophils isolated from the bone marrow of myeloid-targeted HIF-1 knockout mice displayed a marked reduction in survival under hypoxic conditions (37). The mechanism(s) by which HIF-1 regulates neutrophil survival remains to be fully elucidated though work by our group has pointed to a potential role of HIF-1–dependent regulation of IKK and NF-B, known regulators of apoptotic thresholds in neutrophils, and also PGK, a key enzyme involved in glycolysis (37). With recent studies showing that pharmacologic strategies to drive neutrophil apoptosis can result in enhanced resolution of inflammation in vivo (38), targeting the HIF pathway may represent an important therapeutic option for the treatment of myeloid cell–mediated inflammation.

	AN OXYGEN-INDEPENDENT ROLE FOR THE HIF/VHL PATHWAY IN THE REGULATION OF HOST DEFENSE AND INFLAMMATION

Top Abstract CLINICAL RELEVANCE OXYGEN AND EUKARYOTES HIF AND OXYGEN SENSING GLYCOLYSIS AND INFLAMMATION NEUTROPHIL APOPTOSIS AND... AN OXYGEN-INDEPENDENT ROLE FOR... DOWNSTREAM HIF-1{alpha}... CONCLUSIONS References

 
In the light of the role of HIF-1 in the regulation of bacterial killing in vitro and the metabolic shift to glycolysis in myeloid cells, Peyssonnaux and coworkers studied the importance of HIF-1 in the regulation of phagocytic bactericidal capacity in vivo (34). They described a decreased bactericidal activity and exaggerated systemic spread of infection from an initial tissue focus in conditional HIF-1–deficient mice compared with littermate controls. Conversely, in mice deficient for the tumor-suppressor protein von Hippel-Lindau, they show enhanced bactericidal activity and limitation of gram-positive group A Streptococcus infection. Using neutrophils and macrophages isolated from wild-type, HIF-1-null, and VHL-null mice, they also demonstrate HIF-1–dependent regulation of granule protease activity, cathelicidin-related antimicrobial peptide (CRAMP) expression, nitric oxide release, and TNF- production. Importantly, using the human pathogens group A Streptococcus, methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, and Salmonella species they describe the induction of HIF-1 expression and transcriptional activity in macrophages independent of oxygen tension. This work again highlights the role of HIF-1 in coordinating appropriate and effective innate immune responses and describes for the first time the importance of microbial-dependent but oxygen-independent regulation of HIF in myeloid cell–mediated inflammatory responses.

In addition to the oxygen-independent bacterial induction of HIF-1, Peyssonnaux and colleagues have described the induction of HIF-1 protein by lipopolysaccharide (LPS) (39). LPS is a microbial activator of the pattern recognition and pro-inflammatory initiator molecule TLR4 (Toll-like receptor-4) (40). TLRs tailor innate immune responses to pathogens through a family of adapter proteins (41), which ultimately lead to the recruitment of TRAF6 (42) and activation of both NF-B (43) and mitogen-activated protein kinase (MAPK) (44) pathways. TLRs are thus implicated in a number of disease settings including allergic airway inflammation and the sepsis syndrome. Using bone marrow–derived macrophages from a TLR4-deficient mouse, Peyssonnaux and colleagues have shown the TLR4 dependence of LPS-induced HIF-1 protein stabilization (39). This was mirrored by a down-regulation in PHD2 and PHD3 message which, if translated to an active protein level, would provide a mechanism by which HIF-1 protein could escape hydroxylation and targeting to the VHL ubiquitin ligase pathway. Interestingly, they also describe the protective effect of HIF-1 deletion in myeloid cells against intraperitoneal LPS-induced hypotension and hypothermia with a reduction in overall murine mortality at 100 hours. Overall, this would suggest that HIF-1 is a more global regulator of myeloid cell–mediated inflammation and not just restricted to hypoxia signaling. These data are also important, since pathogen subversion of the HIF-1 pathway coupled with the importance of HIF-1 in coordinating an appropriate and effective antimicrobial immune response would suggest that targeting HIF itself potentially risks uncontrolled infection and thus a more selective approach should be considered. This requires a better understanding of the regulators of the HIF pathway both in health and in disease.

Direct evidence that the HIF-1/VHL pathway regulates the innate immune response in humans is provided by a series of experiments using neutrophils derived from patients with von Hippel Lindau disease (45). The VHL tumor syndrome affects 1:36,000 of the population, with patients inheriting a germline mutation in one VHL allele and the disease manifesting after a somatic mutation is acquired in the second remaining VHL allele (46). A close correlation between genotype and tumor predisposition has been described in these families with 70% of mutations being inactivating and the remainder being missense mutations (46, 47). Neutrophils isolated from these individuals are thus heterozygous for VHL expression and hence are predicted to express higher than normal levels of HIF due to inefficient VHL-mediated proteasomal degradation. In keeping with this, circulating neutrophils from these patients have been shown to have a clear "partial hypoxic" phenotype with delayed rates of apoptosis and enhanced bacterial phagocytosis under normoxic conditions (45). These data provide further support for the view that HIF-1 controls several key effector functions in the neutrophil and highlights the close integration of oxygen sensing and inflammatory pathways in myeloid cells.

	DOWNSTREAM HIF-1 INFLAMMATORY TARGETS

Top Abstract CLINICAL RELEVANCE OXYGEN AND EUKARYOTES HIF AND OXYGEN SENSING GLYCOLYSIS AND INFLAMMATION NEUTROPHIL APOPTOSIS AND... AN OXYGEN-INDEPENDENT ROLE FOR... DOWNSTREAM HIF-1{alpha}... CONCLUSIONS References

 
The full spectrum of downstream targets of HIF-1 in myeloid cells remains to be fully elucidated and represents an area of current research. However, vital clues to the importance of parallel signaling pathways are provided by in vitro experiments using transfected cell lines.

NF-B, a key pro-inflammatory transcription regulator, has already been linked to HIF-1–dependent and –independent pro-inflammatory cytokine release by macrophages (48, 39) and also to neutrophil survival under anoxic conditions (37) (with TLR4 dependence in LPS-stimulated macrophages described). More recently, however, the post-translational hydroxylation of ankyrin repeats within both the NF-B repressor protein, IB, and the p105 subunit of NF-B itself by the FIH asparaginyl hydroxylase have been shown (49), directly linking HIF and NF-B pathways. The importance of this interaction in vivo is, however, unknown and made less clear by the lack of any demonstrable functional effect of ankyrin hydroxylation on NF-B activity and NF-B:IB protein interactions. Given the importance of both these signaling cascades in the regulation of inflammation, further work to clarify the importance of cross talk between these pathways at sites of inflammation is clearly required.

The importance of glycolysis in maintaining intracellular ATP pools in both mononuclear cells and neutrophils at sites of inflammation has already been described (33). Recent work detailing the growth factor–dependent regulation of HIF-1 and subsequent decrease in glucose-dependent anabolic synthesis and increase in lactate production (50) lends support to a role for HIF-1 in metabolic and growth factor–stimulated survival that is independent of the ambient oxygen tension. By modulating intracellular glucose utilization, HIF-1 is not purely acting as a cell-intrinsic regulator of glucose metabolism, but may have a more profound role in enabling cells to adapt to changes in oxygen tension, which are of critical importance for their function at sites of tissue injury.

	CONCLUSIONS

Top Abstract CLINICAL RELEVANCE OXYGEN AND EUKARYOTES HIF AND OXYGEN SENSING GLYCOLYSIS AND INFLAMMATION NEUTROPHIL APOPTOSIS AND... AN OXYGEN-INDEPENDENT ROLE FOR... DOWNSTREAM HIF-1{alpha}... CONCLUSIONS References

 
There is now a significant body of evidence linking the PHD-FIH/HIF/VHL oxygen-sensing pathway to the regulation of myeloid cell–mediated inflammatory responses with both oxygen-dependent and -independent roles ascribed. The mechanisms by which HIF and the hydroxylase enzymes moderate mononuclear and neutrophil functional longevity remain poorly understood. Inhibition of HIF-1 activity has been proposed as a novel therapeutic target in a number of disease settings, including the LPS-induced sepsis syndrome, malignancy, and chronic inflammation, but until the downstream targets of HIF-1 have been fully characterized the potential to use HIF-1 antagonists remains limited. Indeed, given its fundamental role in myeloid cell microbicidal activity and the integration of oxygen-sensing pathways with pro-inflammatory responses, targeting HIF-1 itself may be detrimental to the host and a selective downstream or upstream HIF-1 target (e.g., the hydroxylases) may be more desirable. When considering therapeutic options, it is important to remember that a delicate balance exists in vivo between pro- and anti-inflammatory signaling cascades, which may be subverted at any time.

	Footnotes

 
Originally Published in Press as DOI: 10.1165/rcmb.2007-0331TR on October 11, 2007

Conflict of Interest Statement: S.R.W. has received support from AstraZeneca for conference attendance. None of the other authors has a financial relationship in a commercial entity that has an interest in the subject of this manuscript.

Received in original form September 11, 2007

Accepted in final form September 24, 2007

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