Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Interdependence of hypoxic and innate immune responses

Nature Reviews Immunology volume 9, pages 609–617 (2009)Cite this article

Key Points

  • Hypoxia-inducible factor (HIF) is a heterodimeric transcription factor regulated at the protein level by oxygen and iron. Under normoxic conditions HIF is degraded, but under hypoxic conditions or iron restriction HIF is stabilized and can bind specific promoters to drive the expression of genes that are involved in glycolysis, angiogenesis and other adaptive programmes for surviving in conditions of hypoxic stress.

  • Increased expression of HIF is observed in cells and tissues in response to infection with diverse infectious microorganisms. Infectious and necrotic tissue foci are themselves hypoxic or anoxic microenvironments.

  • Conditional gene targeting strategies have now revealed that HIF controls various innate immune response genes and cellular processes that aid in pathogen clearance. These include chemotaxis, phagocytosis, antimicrobial peptide production, granule protease release, nitric oxide production and generation of pro-inflammatory cytokines.

  • HIF innate immune activities are evident not only in phagocytic cells such as macrophages and neutrophils but also in dendritic cells, mast cells and epithelial cells with important host defence functions.

  • Analysis of the mechanisms of HIF activation has revealed links between the ancient stress responses of innate immunity and hypoxic adaptation, as nuclear factor-κB controls HIF1α expression at the transcriptional level.

  • Because of its rapid turnover and well-understood mechanism of post-translational stabilization, HIF is a pharmacologically tractable target for enhancing innate immune defence.

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-κB, 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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Mechanisms of HIF stabilization.
Figure 2: HIF regulation of phagocyte innate immune functions.

Similar content being viewed by others

References

  1. Saadi, S., Wrenshall, L. E. & Platt, J. L. Regional manifestations and control of the immune system. FASEB J. 16, 849–856 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Schor, H., Vaday, G. G. & Lider, O. Modulation of leukocyte behavior by an inflamed extracellular matrix. Dev. Immunol. 7, 227–238 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Vogelberg, K. H. & Konig, M. Hypoxia of diabetic feet with abnormal arterial blood flow. Clin. Invest. 71, 466–470 (1993).

    Article  CAS  Google Scholar 

  4. Arnold, F., West, D. & Kumar, S. Wound healing: the effect of macrophage and tumour derived angiogenesis factors on skin graft vascularization. Br. J. Exp. Pathol. 68, 569–574 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Negus, R. P., Stamp, G. W., Hadley, J. & Balkwill, F. R. Quantitative assessment of the leukocyte infiltrate in ovarian cancer and its relationship to the expression of C-C chemokines. Am. J. Pathol. 150, 1723–1734 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Semenza, G. L. & Wang, G. L. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol. Cell. Biol. 12, 5447–5454 (1992). The landmark initial discovery of the HIFtranscription factor.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wang, G. L., Jiang, B. H., Rue, E. A. & Semenza, G. L. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc. Natl Acad. Sci. USA 92, 5510–5514 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Weidemann, A. & Johnson, R. S. Biology of HIF-1α. Cell Death Differ. 15, 621–627 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Maxwell, P. H. The HIF pathway in cancer. Semin. Cell Dev. Biol. 16, 523–530 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Bruick, R. K. & McKnight, S. L. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294, 1337–1340 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Jaakkola, P. et al. Targeting of HIF-1α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292, 468–472 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Lando, D. et al. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev. 16, 1466–1471 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Peet, D. & Linke, S. Regulation of HIF: asparaginyl hydroxylation. Novartis Found. Symp. 272, 37–49 (2006).

    CAS  Google Scholar 

  14. Fukuda, R. et al. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell 129, 111–122 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Semenza, G. L., Roth, P. H., Fang, H. M. & Wang, G. L. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J. Biol. Chem. 269, 23757–23763 (1994).

    CAS  PubMed  Google Scholar 

  16. Shimoda, L. A., Fallon, M., Pisarcik, S., Wang, J. & Semenza, G. L. HIF-1 regulates hypoxic induction of NHE1 expression and alkalinization of intracellular pH in pulmonary arterial myocytes. Am. J. Physiol. Lung Cell. Mol. Physiol. 291, L941–L949 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Iyer, N. V. et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1α. Genes Dev. 12, 149–162 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ryan, H. E., Lo, J. & Johnson, R. S. HIF-1α is required for solid tumor formation and embryonic vascularization. EMBO J. 17, 3005–3015 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kotch, L. E., Iyer, N. V., Laughner, E. & Semenza, G. L. Defective vascularization of HIF-1α-null embryos is not associated with VEGF deficiency but with mesenchymal cell death. Dev. Biol. 209, 254–267 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Cramer, T. et al. HIF-1α is essential for myeloid cell-mediated inflammation. Cell 112, 645–657 (2003). Myeloid-specific gene targeting identifies an essential role for HIF1α in regulating the inflammatory functions of neutrophils and macrophages.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hollander, A. P., Corke, K. P., Freemont, A. J. & Lewis, C. E. Expression of hypoxia-inducible factor 1α by macrophages in the rheumatoid synovium: implications for targeting of therapeutic genes to the inflamed joint. Arthritis Rheum. 44, 1540–1544 (2001). Clinicopathological indication that HIF1α activity is prominent in the inflammatory lesions of rheumatoid arthritis.

    Article  CAS  PubMed  Google Scholar 

  22. Westra, J. et al. Regulation of cytokine-induced HIF-1α expression in rheumatoid synovial fibroblasts. Ann. NY Acad. Sci. 1108, 340–348 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Konttinen, Y. T. et al. Disease-associated increased HIF-1, αvβ3 integrin, and Flt-1 do not suffice to compensate the damage-inducing loss of blood vessels in inflammatory myopathies. Rheumatol. Int. 24, 333–339 (2004).

    Article  PubMed  Google Scholar 

  24. Clancy, R. M. et al. Role of hypoxia and cAMP in the transdifferentiation of human fetal cardiac fibroblasts: implications for progression to scarring in autoimmune-associated congenital heart block. Arthritis Rheum. 56, 4120–4131 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Vink, A. et al. HIF-1α expression is associated with an atheromatous inflammatory plaque phenotype and upregulated in activated macrophages. Atherosclerosis 195, e69–e75 (2007). This article shows the potential link of HIF1α to the inflammatory aetiology of atherosclerosis.

    Article  CAS  PubMed  Google Scholar 

  26. Peyssonnaux, C. et al. HIF-1α expression regulates the bactericidal capacity of phagocytes. J. Clin. Invest. 115, 1806–1815 (2005). This study shows that HIF1α is essential for macrophage and neutrophil bactericidal activities and host defence against infection with invasive bacteria.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kong, T., Eltzschig, H. K., Karhausen, J., Colgan, S. P. & Shelley, C. S. Leukocyte adhesion during hypoxia is mediated by HIF-1-dependent induction of β2 integrin gene expression. Proc. Natl Acad. Sci. USA 101, 10440–10445 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Walmsley, S. R. et al. Hypoxia-induced neutrophil survival is mediated by HIF-1α-dependent NF-κB activity. J. Exp. Med. 201, 105–115 (2005). This paper indicates that HIF1α delays neutrophil apoptosis to help sustain the local innate immune response.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Walmsley, S. R. et al. Neutrophils from patients with heterozygous germline mutations in the von Hippel Lindau protein (pVHL) display delayed apoptosis and enhanced bacterial phagocytosis. Blood 108, 3176–3178 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Oda, T. et al. Activation of hypoxia-inducible factor 1 during macrophage differentiation. Am. J. Physiol. Cell Physiol. 291, C104–C113 (2006).

    CAS  Google Scholar 

  31. Anand, R. J. et al. Hypoxia causes an increase in phagocytosis by macrophages in a HIF-1α -dependent manner. J. Leukoc. Biol. 82, 1257–1265 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Kuhlicke, J., Frick, J. S., Morote-Garcia, J. C., Rosenberger, P. & Eltzschig, H. K. Hypoxia inducible factor (HIF)-1 coordinates induction of Toll-like receptors TLR2 and TLR6 during hypoxia. PLoS ONE 2, e1364 (2007).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Jantsch, J. et al. Hypoxia and hypoxia-inducible factor-1α modulate lipopolysaccharide-induced dendritic cell activation and function. J. Immunol. 180, 4697–4705 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Hacker, H. & Karin, M. Regulation and function of IKK and IKK-related kinases. Sci. STKE re13 (2006).

  35. Peyssonnaux, C. et al. Cutting edge: essential role of hypoxia inducible factor-1α in development of lipopolysaccharide-induced sepsis. J. Immunol. 178, 7516–7519 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Cummins, E. P. et al. Prolyl hydroxylase-1 negatively regulates IκB kinase-β, giving insight into hypoxia-induced NFκB activity. Proc. Natl Acad. Sci. USA 103, 18154–18159 (2006). An important mechanistic analysis of NF-κB activation under hypoxic conditions is reported in this paper.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Frede, S., Stockmann, C., Freitag, P. & Fandrey, J. Bacterial lipopolysaccharide induces HIF-1 activation in human monocytes via p44/42 MAPK and NF-κB. Biochem. J. 396, 517–527 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Belaiba, R. S. et al. Hypoxia up-regulates hypoxia-inducible factor-1α transcription by involving phosphatidylinositol 3-kinase and nuclear factor κB in pulmonary artery smooth muscle cells. Mol. Biol. Cell 18, 4691–4697 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Rius, J. et al. NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α. Nature 453, 807–811 (2008). NF-κB is shown to be essential for HIF1α upregulation at the mRNA level in response to hypoxia or infection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fang, H. Y. et al. Hypoxia inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia. Blood 114, 844–859 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Mi, Z. et al. Synergystic induction of HIF-1α transcriptional activity by hypoxia and lipopolysaccharide in macrophages. Cell Cycle 7, 232–241 (2008).

    Article  CAS  PubMed  Google Scholar 

  42. Goodarzi, H., Trowbridge, J. & Gallo, R. L. Innate immunity: a cutaneous perspective. Clin. Rev. Allergy Immunol. 33, 15–26 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Braff, M. H., Zaiou, M., Fierer, J., Nizet, V. & Gallo, R. L. Keratinocyte production of cathelicidin provides direct activity against bacterial skin pathogens. Infect. Immun. 73, 6771–6781 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Peyssonnaux, C. et al. Critical role of HIF-1α in keratinocyte defense against bacterial infection. J. Invest. Dermatol. 128, 1964–1968 (2008).

    Article  CAS  PubMed  Google Scholar 

  45. Koury, J. et al. Persistent HIF-1α activation in gut ischemia/reperfusion injury: potential role of bacteria and lipopolysaccharide. Shock 22, 270–277 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Shah, Y. M. et al. Hypoxia-inducible factor augments experimental colitis through an MIF-dependent inflammatory signaling cascade. Gastroenterology 134, 2036–2048 (2008).

    Article  PubMed  Google Scholar 

  47. Karhausen, J. et al. Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis. J. Clin. Invest. 114, 1098–1106 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Robinson, A. et al. Mucosal protection by hypoxia-inducible factor prolyl hydroxylase inhibition. Gastroenterology 134, 145–155 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Cummins, E. P. et al. The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis. Gastroenterology 134, 156–165 (2008).

    Article  CAS  PubMed  Google Scholar 

  50. Rao, K. N. & Brown, M. A. Mast cells: multifaceted immune cells with diverse roles in health and disease. Ann. NY Acad. Sci. 1143, 83–104 (2008).

    Article  CAS  PubMed  Google Scholar 

  51. Jeong, H. J. et al. Expression of proinflammatory cytokines via HIF-1α and NF-κB activation on desferrioxamine-stimulated HMC-1 cells. Biochem. Biophys. Res. Commun. 306, 805–811 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Lee, K. S. et al. Mast cells can mediate vascular permeability through regulation of the PI3K-HIF-1α-VEGF axis. Am. J. Respir. Crit. Care Med. 178, 787–797 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Jeong, H. J. et al. Activation of hypoxia-inducible factor-1 regulates human histidine decarboxylase expression. Cell. Mol. Life Sci. 66, 1309–1319 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. Lukashev, D. et al. Cutting edge: hypoxia-inducible factor 1α and its activation-inducible short isoform I.1 negatively regulate functions of CD4+ and CD8+ T lymphocytes. J. Immunol. 177, 4962–4965 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Thiel, M. et al. Targeted deletion of HIF-1α gene in T cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival. PLoS ONE 2, e853 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Lukashev, D. & Sitkovsky, M. Preferential expression of the novel alternative isoform I.3 of hypoxia-inducible factor 1α in activated human T lymphocytes. Hum. Immunol. 69, 421–425 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Biju, M. P. et al. Vhlh gene deletion induces HIF-1-mediated cell death in thymocytes. Mol. Cell. Biol. 24, 9038–9047 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kilani, M. M., Mohammed, K. A., Nasreen, N., Tepper, R. S. & Antony, V. B. RSV causes HIF-1α stabilization via NO release in primary bronchial epithelial cells. Inflammation 28, 245–251 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Hwang, II, Watson, I. R., Der, S. D. & Ohh, M. Loss of VHL confers hypoxia-inducible factor (HIF)-dependent resistance to vesicular stomatitis virus: role of HIF in antiviral response. J. Virol. 80, 10712–10723 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Yoo, Y. G. et al. Hepatitis B virus X protein enhances transcriptional activity of hypoxia-inducible factor-1α through activation of mitogen-activated protein kinase pathway. J. Biol. Chem. 278, 39076–39084 (2003).

    Article  CAS  PubMed  Google Scholar 

  61. Moon, E. J. et al. Hepatitis B virus X protein induces angiogenesis by stabilizing hypoxia-inducible factor-1α. FASEB J. 18, 382–384 (2004). This study shows that a specific protein virulence factor from an oncogenic virus can stabilize HIF1α.

    Article  CAS  PubMed  Google Scholar 

  62. Nasimuzzaman, M., Waris, G., Mikolon, D., Stupack, D. G. & Siddiqui, A. Hepatitis C virus stabilizes hypoxia-inducible factor 1α and stimulates the synthesis of vascular endothelial growth factor. J. Virol. 81, 10249–10257 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Tang, X. et al. Overexpression of human papillomavirus type 16 oncoproteins enhances hypoxia-inducible factor 1α protein accumulation and vascular endothelial growth factor expression in human cervical carcinoma cells. Clin. Cancer Res. 13, 2568–2576 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Lu, Z. H., Wright, J. D., Belt, B., Cardiff, R. D. & Arbeit, J. M. Hypoxia-inducible factor-1 facilitates cervical cancer progression in human papillomavirus type 16 transgenic mice. Am. J. Pathol. 171, 667–681 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Birner, P. et al. Overexpression of hypoxia-inducible factor 1α is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res. 60, 4693–4696 (2000). Clinicopathological evidence for HIF1α activation in a virus-associated cancer.

    CAS  PubMed  Google Scholar 

  66. Tomita, M. et al. Activation of hypoxia-inducible factor 1 in human T-cell leukaemia virus type 1-infected cell lines and primary adult T-cell leukaemia cells. Biochem. J. 406, 317–323 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wakisaka, N. et al. Epstein-Barr virus latent membrane protein 1 induces synthesis of hypoxia-inducible factor 1α. Mol. Cell. Biol. 24, 5223–5234 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kondo, S. et al. EBV latent membrane protein 1 up-regulates hypoxia-inducible factor 1α through Siah1-mediated down-regulation of prolyl hydroxylases 1 and 3 in nasopharyngeal epithelial cells. Cancer Res. 66, 9870–9877 (2006).

    Article  CAS  PubMed  Google Scholar 

  69. Carroll, P. A., Kenerson, H. L., Yeung, R. S. & Lagunoff, M. Latent Kaposi's sarcoma-associated herpesvirus infection of endothelial cells activates hypoxia-induced factors. J. Virol. 80, 10802–10812 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Cai, Q. et al. Kaposi's sarcoma-associated herpesvirus latent protein LANA interacts with HIF-1α to upregulate RTA expression during hypoxia: latency control under low oxygen conditions. J. Virol. 80, 7965–7975 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Bayele, H. K. et al. HIF-1 regulates heritable variation and allele expression phenotypes of the macrophage immune response gene SLC11A1 from a Z-DNA forming microsatellite. Blood 110, 3039–3048 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Hartmann, H. et al. Hypoxia-independent activation of HIF-1 by enterobacteriaceae and their siderophores. Gastroenterology 134, 756–767 (2008).

    Article  CAS  PubMed  Google Scholar 

  73. Kempf, V. A. et al. Activation of hypoxia-inducible factor-1 in bacillary angiomatosis: evidence for a role of hypoxia-inducible factor-1 in bacterial infections. Circulation 111, 1054–1062 (2005).

    Article  CAS  PubMed  Google Scholar 

  74. Rupp, J. et al. Chlamydia pneumoniae directly interferes with HIF-1α stabilization in human host cells. Cell. Microbiol. 9, 2181–2191 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Spear, W. et al. The host cell transcription factor hypoxia-inducible factor 1 is required for Toxoplasma gondii growth and survival at physiological oxygen levels. Cell. Microbiol. 8, 339–352 (2006). A parasitic pathogen is found to depend on HIF1α for its intracellular survival advantage.

    Article  CAS  PubMed  Google Scholar 

  76. Blader, I. J., Manger, I. D. & Boothroyd, J. C. Microarray analysis reveals previously unknown changes in Toxoplasma gondii-infected human cells. J. Biol. Chem. 276, 24223–24231 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Arrais-Silva, W. W., Paffaro, V. A., Yamada, A. T. & Giorgio, S. Expression of hypoxia-inducible factor-1α in the cutaneous lesions of BALB/c mice infected with Leishmania amazonensis. Exp. Mol. Pathol. 78, 49–54 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Mohamed, H. S. et al. SLC11A1 (formerly NRAMP1) and susceptibility to visceral leishmaniasis in The Sudan. Eur. J. Hum. Genet. 12, 66–74 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Li, H. T., Zhang, T. T., Zhou, Y. Q., Huang, Q. H. & Huang, J. SLC11A1 (formerly NRAMP1) gene polymorphisms and tuberculosis susceptibility: a meta-analysis. Int. J. Tuberc. Lung Dis. 10, 3–12 (2006).

    CAS  PubMed  Google Scholar 

  80. Runstadler, J. A. et al. Association of SLC11A1 (NRAMP1) with persistent oligoarticular and polyarticular rheumatoid factor-negative juvenile idiopathic arthritis in Finnish patients: haplotype analysis in Finnish families. Arthritis Rheum. 52, 247–256 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Takahashi, K. et al. Promoter polymorphism of SLC11A1 (formerly NRAMP1) confers susceptibility to autoimmune type 1 diabetes mellitus in Japanese. Tissue Antigens 63, 231–236 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Strieter, R. M. Mastering innate immunity. Nature Med. 9, 512–513 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Zarember, K. A. & Malech, H. L. HIF-1α: a master regulator of innate host defenses? J. Clin. Invest. 115, 1702–1704 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Zinkernagel, A. S., Peyssonnaux, C., Johnson, R. S. & Nizet, V. Pharmacologic augmentation of hypoxia-inducible factor-1α with mimosine boosts the bactericidal capacity of phagocytes. J. Infect. Dis. 197, 214–217 (2008).

    Article  CAS  PubMed  Google Scholar 

  85. Nizet, V. Understanding how leading bacterial pathogens subvert innate immunity to reveal novel therapeutic targets. J. Allergy Clin. Immunol. 120, 13–22 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Hsieh, M. M. et al. HIF prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques. Blood 110, 2140–2147 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Botusan, I. R. et al. Stabilization of HIF-1α is critical to improve wound healing in diabetic mice. Proc. Natl Acad. Sci. USA 105, 19426–19431 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors' studies in the area of HIF and innate immunity have been supported by US National Institutes of Health grant AI060840 and the American Asthma Foundation.

Author information

Author notes

  1. Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA. vnizet@ucsd.edu; rsjohnson@ucsd.edu

Authors and Affiliations

  1. Department of Pediatrics, 9500 Gilman Drive, La Jolla, 92093, California, USA

    Victor Nizet & Randall S. Johnson

  2. Skaggs School of Pharmacy and Pharmaceutical Sciences, 9500 Gilman Drive, La Jolla, 92093, California, USA

    Victor Nizet

Authors
  1. Victor Nizet
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Randall S. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Randall S. Johnson's homepage

Victor Nizet's homepage

Glossary

Ubiquitin–proteasome pathway

An important proteolytic pathway that involves the tagging of unwanted proteins with ubiquitin, which allows their recognition by the proteasome — a large, multi-component protein-degrading complex.

Cre recombinase

A site-specific recombinase that recognizes and binds specific sites known as LoxP. Two LoxP sites recombine in the presence of Cre, allowing DNA that is cloned between two such sites to be removed by Cre-mediated recombination.

Cathelicidins

Mammalian cationic microbicidal peptides expressed by epithelial cells and phagocytes that share a highly conserved 'cathelin' 12 kDa pro-sequence at the amino terminus, followed by diversified mature sequences at the carboxyl terminus. Activation of most cathelicidin precursors requires proteolytic cleavage to release the C-terminal domain, which has microbicidal and immunomodulatory activities.

Ischaemia–reperfusion injury

An injury in which the tissue first suffers from hypoxia as a result of severely decreased, or completely arrested, blood flow. Restoration of normal blood flow then triggers inflammation, which exacerbates the tissue damage.

Caecal ligation and puncture

An experimental model of peritonitis in rodents, in which the caecum is ligated and then punctured. This leads to leakage of intestinal bacteria into the peritoneal cavity and subsequent peritoneal infection.

Siderophores

Low-molecular-mass compounds that are secreted by numerous types of bacteria and that have a high affinity for iron and other metal ions. These molecules chelate metal ions and carry them into the cell through specific receptors, promoting bacterial survival in the host.

Z-DNA-forming microsatellite polymorphisms

Microsatellites such as the SLC11A1 (GT/CA)n dinucleotide repeat tend to form Z-DNA, an unstable left-handed form of DNA that is transiently induced during gene transcription by a moving RNA polymerase and stabilized by negative supercoiling. Polymorphisms in such microsatellites can activate or repress gene transcription in a context-dependent manner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nizet, V., Johnson, R. Interdependence of hypoxic and innate immune responses. Nat Rev Immunol 9, 609–617 (2009). https://doi.org/10.1038/nri2607

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2607

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing