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Review
. 2011 Feb 17;364(7):656-65.
doi: 10.1056/NEJMra0910283.

Hypoxia and inflammation

Holger K Eltzschig  1 , Peter Carmeliet
Affiliations
Review

Hypoxia and inflammation

Holger K Eltzschig et al. N Engl J Med. .
No abstract available

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Figures

Figure 1
Figure 1. Links between Hypoxia and Inflammation
Shown is an overview of clinical conditions characterized primarily by tissue hypoxia that causes inflammatory changes (left) and inflammatory diseases leading to tissue hypoxia (right).
Figure 2
Figure 2. Schematic Overview of the Molecular Interaction between the HIF and (Canonical) NF-κB Pathways
In hypoxic conditions (left), hypoxia-inducible factor (HIF) α and HIF-β subunits translocate to the nucleus, where they bind as heterodimers to a hypoxia response promoter element (HRE), inducing transcription of numerous genes, including those of nuclear factor κB (NF-κB) and toll-like receptors (TLRs). In normoxia, HIF-α is hydroxylated by prolyl hydroxylases (PHDs) and factor-inhibiting HIF (FIH) and is thereby targeted for proteasomal degradation (in the case of PHDs) or rendered transcriptionally less active (in the case of FIH; not shown here). In resting cells (right), NF-κB, a heterodimer consisting of p50 and p65 subunits, is inactive in the cytosol because it is associated with nuclear factor of kappa light polypeptide gene enhancer in B cells alpha (IκBα), a regulatory component of NF-κB. At the time of cellular activation, the beta subunit of the IκB kinase complex (IKKβ) phosphorylates the inhibitor IκBα, which thereby becomes degraded and liberates NF-κB for translocation in the nucleus, where it can activate the transcription of inflammatory genes as well as of HIF (genes involved in tissue protection and homeostasis are not shown). PHDs and FIH regulate NF-κB activation by controlling the activity of IKKβ.
Figure 3
Figure 3. Influence of Hypoxia on the Innate and Adaptive Immune Systems
In the example shown in this schematic overview, the epithelium (left) is breached by invading pathogens, leading to tissue damage; as a result, innate immune cells mount a host defense response, which is amplified by recruited adaptive immune cells. In general, hypoxia amplifies the activity of innate immune cells while suppressing the response of the adaptive immune system, in part by promoting differentiation of regulatory T cells and negatively regulating the function of CD4+ helper T (Th) cells and CD8+ cytotoxic T cells and the polarization of type 1 Th (Th1) cells. By negatively regulating adaptive immunity, hypoxia prevents excessive activation of the immune host defense, which might otherwise lead to collateral tissue damage.
Figure 4
Figure 4. Schematic Overview of the Link between Hypoxia and Inflammation in Cancer
In tumor cells, oncogenes, inflammatory signals (mediated in part through toll-like receptors [TLRs]), and hypoxia activate nuclear factor κB (NF-κB) and hypoxia-inducible factor (HIF) 1α (which activate each other). These factors induce a gene program that recruits and activates leukocytes (through release of chemokines and cytokines), stimulates angiogenesis and the formation of an abnormal vasculature and endothelium (through release of angiogenic signals), and increases tumor-cell invasion, metastasis, epithelial-to-mesenchymal transition (EMT), survival, proliferation, and metabolic reprogramming. In leukocytes, hypoxia also activates NF-κB and HIF-1α; endogenous ligands, released from necrotic cancer cells, activate TLRs upstream of NF-κB and HIF-1α, and HIF-1α up-regulates TLR expression. A resultant gene-expression profile leads to the production of cytokines and angiogenic signals and skews their polarization phenotype. Tumor vessels with two prolyl hydroxylase (PHD) domain 2 (PHD2) alleles have an abnormal endothelium, are hypoperfused, and cause tumor hypoxia, which fuels tumor-cell invasiveness and metastasis. In contrast, tumor vessels lacking one PHD2 allele have increased HIF-2α levels, which result in an up-regulation of factors that counteract the development of tumor endothelial abnormalities; this, in turn, results in improved tumor-vessel perfusion and oxygenation and, secondarily, reduced metastasis.
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Comment in

  • Hypoxia and inflammation.
    Wilcox I, Chan KH, Lattimore JD. Wilcox I, et al. N Engl J Med. 2011 May 19;364(20):1976-7; author reply 1977. doi: 10.1056/NEJMc1103019. N Engl J Med. 2011. PMID: 21591956 No abstract available.
  • Hypoxia and inflammation.
    Fagenholz PJ, Harris NS. Fagenholz PJ, et al. N Engl J Med. 2011 May 19;364(20):1976; author reply 1977. doi: 10.1056/NEJMc1103019. N Engl J Med. 2011. PMID: 21591957 No abstract available.
  • Hypoxia and inflammation.
    Wanderer AA. Wanderer AA. N Engl J Med. 2011 May 19;364(20):1976; author reply 1977. doi: 10.1056/NEJMc1103019. N Engl J Med. 2011. PMID: 21591958 No abstract available.

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