Hypoxia-induced neutrophil survival is mediated by HIF-1α–dependent NF-κB activity

Abstract

Neutrophils are key effector cells of the innate immune response and are required to migrate and function within adverse microenvironmental conditions. These inflammatory sites are characterized by low levels of oxygen and glucose and high levels of reductive metabolites. A major regulator of neutrophil functional longevity is the ability of these cells to undergo apoptosis. We examined the mechanism by which hypoxia causes an inhibition of neutrophil apoptosis in human and murine neutrophils. We show that neutrophils possess the hypoxia-inducible factor (HIF)-1α and factor inhibiting HIF (FIH) hydroxylase oxygen-sensing pathway and using HIF-1α–deficient myeloid cells demonstrate that HIF-1α is directly involved in regulating neutrophil survival in hypoxia. Gene array, TaqMan PCR, Western blotting, and oligonucleotide binding assays identify NF-κB as a novel hypoxia-regulated and HIF-dependent target, with inhibition of NF-κB by gliotoxin or parthenolide resulting in the abrogation of hypoxic survival. In addition, we identify macrophage inflammatory protein-1β as a novel hypoxia-induced neutrophil survival factor.

Hypoxic regulation of neutrophil function and consequences for Staphylococcus aureus infection

“…HIF-1a and HIF2a regulate distinct but overlapping target gene sets, with HIF1a having a greater impact upon immediate metabolic targets. In hypoxic culture, neutrophils upregulate glycolytic HIF-1a target genes, such as glyceraldehyde 3-phosphate dehydrogenase and phosphoglycerate kinase [36]. Indeed, neutrophils deficient in HIF-1a have reduced ATP levels even under normoxic conditions, reflecting the importance of HIF-1a in the regulation of neutrophil energetics [37].…”

“…Indeed, neutrophils deficient in HIF-1a have reduced ATP levels even under normoxic conditions, reflecting the importance of HIF-1a in the regulation of neutrophil energetics [37]. It is therefore not surprising that HIF-1a is essential for extended neutrophil survival in hypoxia [36]. Notably, deficiency of HIF-2a impairs neither neutrophil survival in hypoxia nor key neutrophil functions, suggesting that HIF-2a plays a less prominent role in the control of hypoxic neutrophil responses.…”

Hypoxia and gastrointestinal disease

“…Thus, inflammatory stimuli activate the HIF pathway through transcriptional upregulation of the HIF-1 mRNA expression in an NF-κB-dependent manner. Conversely, NF-κB activity in hypoxia can be regulated by HIF [37]. Clearly, an intimate relationship exists between NF-κB and HIF-1 signaling in the context of microenvironments where hypoxia and inflammation coexist such as the inflamed bowel.…”

NFκB and HIF display synergistic behaviour during hypoxic inflammation

“…NF!B can also regulate HIF-2# signalling through an interaction with the NF!B essential modulator (NEMO), which aids in the recruitment of transcriptional co-activators such as CREB binding protein (CBP) and p300, and increases HIF-2# transcriptional activity [19]. Conversely HIF-1# has been reported to alter NF!B signalling in neutrophils [20]. In addition, a group of proinflammatory genes, including cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS) contains functional response elements for both HIF and NF!B in their promoter regions.…”