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:

Intestinal hypoxia and hypoxia-induced signalling as therapeutic targets for IBD

Nature Reviews Gastroenterology & Hepatology volume 14, pages 596–611 (2017)Cite this article

Subjects

Key Points

  • Mucosal hypoxia is an integral component of IBD

  • Hypoxia-induced signalling by hypoxia-inducible factors and nuclear factor-κB can promote or counteract the intestinal inflammatory response, depending on the context and cell type studied

  • Oxygen-sensitive prolyl hydroxylases (PHDs) tightly regulate hypoxia-induced signalling pathways and have been identified as promising therapeutic targets in IBD

  • Pan-hydroxylase inhibitors are in an advanced stage of development for the treatment of anaemia related to chronic kidney disease and are in phase I trials for the treatment of ulcerative colitis

  • The use of orally administered and isotype-specific PHD inhibitors might reduce systemic exposure and the risk of unwanted side-effects

Abstract

Tissue hypoxia occurs when local oxygen demand exceeds oxygen supply. In chronic inflammatory conditions such as IBD, the increased oxygen demand by resident and gut-infiltrating immune cells coupled with vascular dysfunction brings about a marked reduction in mucosal oxygen concentrations. To counter the hypoxic challenge and ensure their survival, mucosal cells induce adaptive responses, including the activation of hypoxia-inducible factors (HIFs) and modulation of nuclear factor-κB (NF-κB). Both pathways are tightly regulated by oxygen-sensitive prolyl hydroxylases (PHDs), which therefore represent promising therapeutic targets for IBD. In this Review, we discuss the involvement of mucosal hypoxia and hypoxia-induced signalling in the pathogenesis of IBD and elaborate in detail on the role of HIFs, NF-κB and PHDs in different cell types during intestinal inflammation. We also provide an update on the development of PHD inhibitors and discuss their therapeutic potential in IBD.

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: Regulation of HIF and the canonical arm of the NF-κB pathway through PHDs and FIH.
Figure 2: The hypoxia-induced proinflammatory response versus the adaptive response in various cell types.

Similar content being viewed by others

References

  1. 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 

  2. Hindryckx, P. et al. Absence of placental growth factor blocks dextran sodium sulfate-induced colonic mucosal angiogenesis, increases mucosal hypoxia and aggravates acute colonic injury. Lab Invest. 90, 566–576 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Giatromanolaki, A. et al. Hypoxia inducible factor 1α and 2α overexpression in inflammatory bowel disease. J. Clin. Pathol. 56, 209–213 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Schreiber, S., Nikolaus, S. & Hampe, J. Activation of nuclear factor κB inflammatory bowel disease. Gut 42, 477–484 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Xu, C. & Dong, W. Role of hypoxia-inducible factor-1α in pathogenesis and disease evaluation of ulcerative colitis. Exp. Ther. Med. 11, 1330–1334 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Taylor, C. T. & Colgan, S. P. Hypoxia and gastrointestinal disease. J. Mol. Med. (Berl.) 85, 1295–1300 (2007).

    Article  Google Scholar 

  7. Fisher, E. M., Khan, M., Salisbury, R. & Kuppusamy, P. Noninvasive monitoring of small intestinal oxygen in a rat model of chronic mesenteric ischemia. Cell Biochem. Biophys. 67, 451–459 (2013).

    Article  CAS  PubMed  Google Scholar 

  8. Zeitouni, N. E., Chotikatum, S., von Kockritz-Blickwede, M. & Naim, H. Y. The impact of hypoxia on intestinal epithelial cell functions: consequences for invasion by bacterial pathogens. Mol. Cell Pediatr. 3, 14 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Campbell, E. L. et al. Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation. Immunity 40, 66–77 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hatoum, O. A., Miura, H. & Binion, D. G. The vascular contribution in the pathogenesis of inflammatory bowel disease. Am. J. Physiol. Heart Circ. Physiol. 285, H1791–H1796 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. 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 

  12. Ivan, M. et al. HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292, 464–468 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Maxwell, P. H. et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271–275 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Biddlestone, J., Bandarra, D. & Rocha, S. The role of hypoxia in inflammatory disease (review). Int. J. Mol. Med. 35, 859–869 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Schofield, C. J. & Ratcliffe, P. J. Oxygen sensing by HIF hydroxylases. Nat. Rev. Mol. Cell Biol. 5, 343–354 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Semenza, G. L. Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1. Biochem. J. 405, 1–9 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Ortiz-Barahona, A., Villar, D., Pescador, N., Amigo, J. & del Peso, L. Genome-wide identification of hypoxia-inducible factor binding sites and target genes by a probabilistic model integrating transcription-profiling data and in silico binding site prediction. Nucleic Acids Res. 38, 2332–2345 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chowdhury, R., Hardy, A. & Schofield, C. J. The human oxygen sensing machinery and its manipulation. Chem. Soc. Rev. 37, 1308–1319 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Stiehl, D. P. et al. Increased prolyl 4-hydroxylase domain proteins compensate for decreased oxygen levels. Evidence for an autoregulatory oxygen-sensing system. J. Biol. Chem. 281, 23482–23491 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Koong, A. C., Chen, E. Y. & Giaccia, A. J. Hypoxia causes the activation of nuclear factor κB through the phosphorylation of IκBα on tyrosine residues. Cancer Res. 54, 1425–1430 (1994).

    CAS  PubMed  Google Scholar 

  21. Taylor, C. T. & Cummins, E. P. The role of NF-κB in hypoxia-induced gene expression. Ann. NY Acad. Sci. 1177, 178–184 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Oliver, K. M. et al. Hypoxia activates NF-κB-dependent gene expression through the canonical signaling pathway. Antioxid. Redox Signal 11, 2057–2064 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Takeda, Y. et al. Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis. Nature 479, 122–126 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Xue, J. et al. Prolyl hydroxylase-3 is down-regulated in colorectal cancer cells and inhibits IKKβ independent of hydroxylase activity. Gastroenterology 138, 606–615 (2010).

    Article  CAS  PubMed  Google Scholar 

  26. Fu, J. & Taubman, M. B. EGLN3 inhibition of NF-κB is mediated by prolyl hydroxylase-independent inhibition of IκB kinase γ ubiquitination. Mol. Cell. Biol. 33, 3050–3061 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Aoki, M. et al. Endothelial apoptosis induced by oxidative stress through activation of NF-κB: antiapoptotic effect of antioxidant agents on endothelial cells. Hypertension 38, 48–55 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Matsui, H. et al. Induction of interleukin (IL)-6 by hypoxia is mediated by nuclear factor (NF)-κB and NF-IL6 in cardiac myocytes. Cardiovasc. Res. 42, 104–112 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Fitzpatrick, S. F. et al. An intact canonical NF-κB pathway is required for inflammatory gene expression in response to hypoxia. J. Immunol. 186, 1091–1096 (2011).

    Article  CAS  PubMed  Google Scholar 

  30. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cockman, M. E. et al. Posttranslational hydroxylation of ankyrin repeats in IκB proteins by the hypoxia-inducible factor (HIF) asparaginyl hydroxylase, factor inhibiting HIF (FIH). Proc. Natl Acad. Sci. USA 103, 14767–14772 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bonello, S. et al. Reactive oxygen species activate the HIF-1α promoter via a functional NFκB site. Arterioscler. Thromb. Vasc. Biol. 27, 755–761 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. van Uden, P., Kenneth, N. S. & Rocha, S. Regulation of hypoxia-inducible factor-1α by NF-κB. Biochem. J. 412, 477–484 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Rius, J. et al. NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α. Nature 453, 807–811 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bracken, C. P., Whitelaw, M. L. & Peet, D. J. Activity of hypoxia-inducible factor 2α is regulated by association with the NF-κB essential modulator. J. Biol. Chem. 280, 14240–14251 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. 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 

  37. Zhou, J., Schmid, T. & Brune, B. Tumor necrosis factor-α causes accumulation of a ubiquitinated form of hypoxia inducible factor-1α through a nuclear factor-κB-dependent pathway. Mol. Biol. Cell 14, 2216–2225 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kim, J. et al. Hypoxia-induced IL-18 increases hypoxia-inducible factor-1α expression through a Rac1-dependent NF-κB pathway. Mol. Biol. Cell 19, 433–444 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Scortegagna, M. et al. HIF-1α regulates epithelial inflammation by cell autonomous NFκB activation and paracrine stromal remodeling. Blood 111, 3343–3354 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Taylor, C. T., Fueki, N., Agah, A., Hershberg, R. M. & Colgan, S. P. Critical role of cAMP response element binding protein expression in hypoxia-elicited induction of epithelial tumor necrosis factor-α. J. Biol. Chem. 274, 19447–19454 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Taylor, C. T., Dzus, A. L. & Colgan, S. P. Autocrine regulation of epithelial permeability by hypoxia: role for polarized release of tumor necrosis factor alpha. Gastroenterology 114, 657–668 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. 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 

  43. Hannah, S. et al. Hypoxia prolongs neutrophil survival in vitro. FEBS Lett. 372, 233–237 (1995).

    Article  CAS  PubMed  Google Scholar 

  44. Mecklenburgh, K. I. et al. Involvement of a ferroprotein sensor in hypoxia-mediated inhibition of neutrophil apoptosis. Blood 100, 3008–3016 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Yun, J. K. et al. Inflammatory mediators are perpetuated in macrophages resistant to apoptosis induced by hypoxia. Proc. Natl Acad. Sci. USA 94, 13903–13908 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kohler, T., Reizis, B., Johnson, R. S., Weighardt, H. & Forster, I. Influence of hypoxia-inducible factor 1α on dendritic cell differentiation and migration. Eur. J. Immunol. 42, 1226–1236 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Blengio, F. et al. The hypoxic environment reprograms the cytokine/chemokine expression profile of human mature dendritic cells. Immunobiology 218, 76–89 (2013).

    Article  CAS  PubMed  Google Scholar 

  48. Bosco, M. C. et al. Hypoxia modulates the gene expression profile of immunoregulatory receptors in human mature dendritic cells: identification of TREM-1 as a novel hypoxic marker in vitro and in vivo. Blood 117, 2625–2639 (2011).

    Article  CAS  PubMed  Google Scholar 

  49. Genua, M., Rutella, S., Correale, C. & Danese, S. The triggering receptor expressed on myeloid cells (TREM) in inflammatory bowel disease pathogenesis. J. Transl Med. 12, 293 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Mishra, K. P., Jain, S., Ganju, L. & Singh, S. B. Hypoxic stress induced TREM-1 and inflammatory chemokines in human peripheral blood mononuclear cells. Indian J. Clin. Biochem. 29, 133–138 (2014).

    Article  CAS  PubMed  Google Scholar 

  51. Michiels, C., Arnould, T., Knott, I., Dieu, M. & Remacle, J. Stimulation of prostaglandin synthesis by human endothelial cells exposed to hypoxia. Am. J. Physiol. 264, C866–C874 (1993).

    Article  CAS  PubMed  Google Scholar 

  52. Michiels, C., Arnould, T. & Remacle, J. Endothelial cell responses to hypoxia: initiation of a cascade of cellular interactions. Biochim. Biophys. Acta 1497, 1–10 (2000).

    Article  CAS  PubMed  Google Scholar 

  53. Ogawa, S. et al. Hypoxia modulates the barrier and coagulant function of cultured bovine endothelium. Increased monolayer permeability and induction of procoagulant properties. J. Clin. Invest. 85, 1090–1098 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Shweiki, D., Itin, A., Soffer, D. & Keshet, E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359, 843–845 (1992).

    Article  CAS  PubMed  Google Scholar 

  55. Scaldaferri, F. et al. VEGF-A links angiogenesis and inflammation in inflammatory bowel disease pathogenesis. Gastroenterology 136, 585–595.e5 (2009).

    Article  CAS  PubMed  Google Scholar 

  56. Furuta, G. T. et al. Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia. J. Exp. Med. 193, 1027–1034 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Colgan, S. P., Dzus, A. L. & Parkos, C. A. Epithelial exposure to hypoxia modulates neutrophil transepithelial migration. J. Exp. Med. 184, 1003–1015 (1996).

    Article  CAS  PubMed  Google Scholar 

  58. Synnestvedt, K. et al. Ecto-5′-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia. J. Clin. Invest. 110, 993–1002 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Louis, N. A. et al. Selective induction of mucin-3 by hypoxia in intestinal epithelia. J. Cell. Biochem. 99, 1616–1627 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. Comerford, K. M. et al. Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res. 62, 3387–3394 (2002).

    CAS  PubMed  Google Scholar 

  61. Kong, T., Westerman, K. A., Faigle, M., Eltzschig, H. K. & Colgan, S. P. HIF-dependent induction of adenosine A2B receptor in hypoxia. FASEB J. 20, 2242–2250 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Eltzschig, H. K. et al. HIF-1-dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia. J. Exp. Med. 202, 1493–1505 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Morote-Garcia, J. C., Rosenberger, P., Nivillac, N. M., Coe, I. R. & Eltzschig, H. K. Hypoxia-inducible factor-dependent repression of equilibrative nucleoside transporter 2 attenuates mucosal inflammation during intestinal hypoxia. Gastroenterology 136, 607–618 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. Aherne, C. M. et al. Epithelial-specific A2B adenosine receptor signaling protects the colonic epithelial barrier during acute colitis. Mucosal Immunol. 8, 1324–1338 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Frick, J. S. et al. Contribution of adenosine A2B receptors to inflammatory parameters of experimental colitis. J. Immunol. 182, 4957–4964 (2009).

    Article  CAS  PubMed  Google Scholar 

  66. Kelly, C. J. et al. Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function. Cell Host Microbe 17, 662–671 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Glover, L. E. et al. Control of creatine metabolism by HIF is an endogenous mechanism of barrier regulation in colitis. Proc. Natl Acad. Sci. USA 110, 19820–19825 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hindryckx, P. et al. Hydroxylase inhibition abrogates TNF-α-induced intestinal epithelial damage by hypoxia-inducible factor-1-dependent repression of FADD. J. Immunol. 185, 6306–6316 (2010).

    Article  CAS  PubMed  Google Scholar 

  69. Kelly, C. J. et al. Fundamental role for HIF-1α in constitutive expression of human β defensin-1. Mucosal Immunol. 6, 1110–1118 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Rosenberger, P. et al. Hypoxia-inducible factor-dependent induction of netrin-1 dampens inflammation caused by hypoxia. Nat. Immunol. 10, 195–202 (2009).

    Article  CAS  PubMed  Google Scholar 

  71. Louis, N. A., Hamilton, K. E., Kong, T. & Colgan, S. P. HIF-dependent induction of apical CD55 coordinates epithelial clearance of neutrophils. FASEB J. 19, 950–959 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Thompson, L. F. et al. Crucial role for ecto-5′-nucleotidase (CD73) in vascular leakage during hypoxia. J. Exp. Med. 200, 1395–1405 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Eltzschig, H. K. et al. Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors. J. Exp. Med. 198, 783–796 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Shah, Y. M. et al. Hypoxia-inducible factor augments experimental colitis through an MIF-dependent inflammatory signaling cascade. Gastroenterology 134, 2036–2048.e3 (2008).

    Article  PubMed  Google Scholar 

  75. Xue, X. et al. Endothelial PAS domain protein 1 activates the inflammatory response in the intestinal epithelium to promote colitis in mice. Gastroenterology 145, 831–841 (2013).

    Article  CAS  PubMed  Google Scholar 

  76. Xie, L. et al. Hypoxia-inducible factor/MAZ-dependent induction of caveolin-1 regulates colon permeability through suppression of occludin, leading to hypoxia-induced inflammation. Mol. Cell. Biol. 34, 3013–3023 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Saeedi, B. J. et al. HIF-dependent regulation of claudin-1 is central to intestinal epithelial tight junction integrity. Mol. Biol. Cell 26, 2252–2262 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Le Bras, A. et al. HIF-2α specifically activates the VE-cadherin promoter independently of hypoxia and in synergy with Ets-1 through two essential ETS-binding sites. Oncogene 26, 7480–7489 (2007).

    Article  CAS  PubMed  Google Scholar 

  79. Coulet, F., Nadaud, S., Agrapart, M. & Soubrier, F. Identification of hypoxia-response element in the human endothelial nitric-oxide synthase gene promoter. J. Biol. Chem. 278, 46230–46240 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Palatka, K. et al. Changes in the expression and distribution of the inducible and endothelial nitric oxide synthase in mucosal biopsy specimens of inflammatory bowel disease. Scand. J. Gastroenterol. 40, 670–680 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Hatoum, O. A., Binion, D. G., Otterson, M. F. & Gutterman, D. D. Acquired microvascular dysfunction in inflammatory bowel disease: Loss of nitric oxide-mediated vasodilation. Gastroenterology 125, 58–69 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Gilkes, D. M., Bajpai, S., Chaturvedi, P., Wirtz, D. & Semenza, G. L. Hypoxia-inducible factor 1 (HIF-1) promotes extracellular matrix remodeling under hypoxic conditions by inducing P4HA1, P4HA2, and PLOD2 expression in fibroblasts. J. Biol. Chem. 288, 10819–10829 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Lokmic, Z., Musyoka, J., Hewitson, T. D. & Darby, I. A. Hypoxia and hypoxia signaling in tissue repair and fibrosis. Int. Rev. Cell. Mol. Biol. 296, 139–185 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Kottmann, R. M. et al. Lactic acid is elevated in idiopathic pulmonary fibrosis and induces myofibroblast differentiation via pH-dependent activation of transforming growth factor-β. Am. J. Respir. Crit. Care Med. 186, 740–751 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. McMahon, S., Charbonneau, M., Grandmont, S., Richard, D. E. & Dubois, C. M. Transforming growth factor β1 induces hypoxia-inducible factor-1 stabilization through selective inhibition of PHD2 expression. J. Biol. Chem. 281, 24171–24181 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Hackenbeck, T. et al. HIF-1 or HIF-2 induction is sufficient to achieve cell cycle arrest in NIH3T3 mouse fibroblasts independent from hypoxia. Cell Cycle 8, 1386–1395 (2009).

    Article  CAS  PubMed  Google Scholar 

  87. Cramer, T. et al. HIF-1α is essential for myeloid cell-mediated inflammation. Cell 112, 645–657 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Peyssonnaux, C. et al. HIF-1α expression regulates the bactericidal capacity of phagocytes. J. Clin. Invest. 115, 1806–1815 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Thompson, A. A. et al. Hypoxia-inducible factor 2α regulates key neutrophil functions in humans, mice, and zebrafish. Blood 123, 366–376 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wera, O., Lancellotti, P. & Oury, C. The dual role of neutrophils in inflammatory bowel diseases. J. Clin. Med. 5, 118 (2016).

    Article  CAS  PubMed Central  Google Scholar 

  91. Mantovani, A. et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25, 677–686 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Sheikh, S. Z. & Plevy, S. E. The role of the macrophage in sentinel responses in intestinal immunity. Curr. Opin. Gastroenterol. 26, 578–582 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Labonte, A. C., Tosello-Trampont, A. C. & Hahn, Y. S. The role of macrophage polarization in infectious and inflammatory diseases. Mol. Cells 37, 275–285 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Galvan-Pena, S. & O'Neill, L. A. Metabolic reprograming in macrophage polarization. Front. Immunol. 5, 420 (2014).

    PubMed  PubMed Central  Google Scholar 

  95. Hu, C. J., Wang, L. Y., Chodosh, L. A., Keith, B. & Simon, M. C. Differential roles of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α in hypoxic gene regulation. Mol. Cell. Biol. 23, 9361–9374 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Kim, S. Y. et al. Hypoxic stress up-regulates the expression of Toll-like receptor 4 in macrophages via hypoxia-inducible factor. Immunology 129, 516–524 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Takeda, N. et al. Differential activation and antagonistic function of HIF-α isoforms in macrophages are essential for NO homeostasis. Genes Dev. 24, 491–501 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Imtiyaz, H. Z. et al. Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation. J. Clin. Invest. 120, 2699–2714 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Wobben, R. et al. Role of hypoxia inducible factor-1α for interferon synthesis in mouse dendritic cells. Biol. Chem. 394, 495–505 (2013).

    Article  CAS  PubMed  Google Scholar 

  100. Naldini, A. et al. Hypoxia affects dendritic cell survival: role of the hypoxia-inducible factor-1α and lipopolysaccharide. J. Cell. Physiol. 227, 587–595 (2012).

    Article  CAS  PubMed  Google Scholar 

  101. Fluck, K., Breves, G., Fandrey, J. & Winning, S. Hypoxia-inducible factor 1 in dendritic cells is crucial for the activation of protective regulatory T cells in murine colitis. Mucosal. Immunol. 9, 379–390 (2016).

    Article  CAS  PubMed  Google Scholar 

  102. Crotty Alexander, L. E. et al. Myeloid cell HIF-1α regulates asthma airway resistance and eosinophil function. J. Mol. Med. (Berl.) 91, 637–644 (2013).

    Article  CAS  Google Scholar 

  103. Sumbayev, V. V., Yasinska, I., Oniku, A. E., Streatfield, C. L. & Gibbs, B. F. Involvement of hypoxia-inducible factor-1 in the inflammatory responses of human LAD2 mast cells and basophils. PLoS ONE 7, e34259 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 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 

  105. Shehade, H., Acolty, V., Moser, M. & Oldenhove, G. Cutting edge: hypoxia-inducible factor 1 negatively regulates Th1 function. J. Immunol. 195, 1372–1376 (2015).

    Article  CAS  PubMed  Google Scholar 

  106. Ben-Shoshan, J., Maysel-Auslender, S., Mor, A., Keren, G. & George, J. Hypoxia controls CD4+CD25+ regulatory T-cell homeostasis via hypoxia-inducible factor-1α. Eur. J. Immunol. 38, 2412–2418 (2008).

    Article  CAS  PubMed  Google Scholar 

  107. Dang, E. V. et al. Control of TH17/Treg balance by hypoxia-inducible factor 1. Cell 146, 772–784 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Higashiyama, M. et al. HIF-1 in T cells ameliorated dextran sodium sulfate-induced murine colitis. J. Leukoc. Biol. 91, 901–909 (2012).

    Article  CAS  PubMed  Google Scholar 

  109. Clambey, E. T. et al. Hypoxia-inducible factor-1α-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc. Natl Acad. Sci. USA 109, E2784–E2793 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Zhang, J. et al. Hypoxia-inducible factor-2α limits natural killer T cell cytotoxicity in renal ischemia/reperfusion injury. J. Am. Soc. Nephrol. 27, 92–106 (2016).

    Article  CAS  PubMed  Google Scholar 

  111. Kojima, H. et al. Abnormal B lymphocyte development and autoimmunity in hypoxia-inducible factor 1α-deficient chimeric mice. Proc. Natl Acad. Sci. USA 99, 2170–2174 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Goda, N. et al. Hypoxia-inducible factor 1α is essential for cell cycle arrest during hypoxia. Mol. Cell. Biol. 23, 359–369 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Cho, S. H. et al. Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system. Nature 537, 234–238 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Hayden, M. S. & Ghosh, S. NF-κB, the first quarter-century: remarkable progress and outstanding questions. Genes Dev. 26, 203–234 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Neurath, M. F., Pettersson, S., Meyer zum Buschenfelde, K. H. & Strober, W. Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF-κB abrogates established experimental colitis in mice. Nat. Med. 2, 998–1004 (1996).

    Article  CAS  PubMed  Google Scholar 

  116. MacMaster, J. F. et al. An inhibitor of IκB kinase, BMS-345541, blocks endothelial cell adhesion molecule expression and reduces the severity of dextran sulfate sodium-induced colitis in mice. Inflamm. Res. 52, 508–511 (2003).

    Article  CAS  PubMed  Google Scholar 

  117. Eckmann, L. et al. Opposing functions of IKKβ during acute and chronic intestinal inflammation. Proc. Natl Acad. Sci. USA 105, 15058–15063 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Hayden, M. S., West, A. P. & Ghosh, S. NF-κB and the immune response. Oncogene 25, 6758–6780 (2006).

    Article  CAS  PubMed  Google Scholar 

  119. Lawrence, T., Gilroy, D. W., Colville-Nash, P. R. & Willoughby, D. A. Possible new role for NF-κB in the resolution of inflammation. Nat. Med. 7, 1291–1297 (2001).

    Article  CAS  PubMed  Google Scholar 

  120. Greten, F. R. et al. NF-κB is a negative regulator of IL-1β secretion as revealed by genetic and pharmacological inhibition of IKKβ. Cell 130, 918–931 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Erdman, S., Fox, J. G., Dangler, C. A., Feldman, D. & Horwitz, B. H. Typhlocolitis in NF-κB-deficient mice. J. Immunol. 166, 1443–1447 (2001).

    Article  CAS  PubMed  Google Scholar 

  122. Tomczak, M. F. et al. Inhibition of Helicobacter hepaticus-induced colitis by IL-10 requires the p50/p105 subunit of NF-κB. J. Immunol. 177, 7332–7339 (2006).

    Article  CAS  PubMed  Google Scholar 

  123. Nenci, A. et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557–561 (2007).

    Article  CAS  PubMed  Google Scholar 

  124. Tambuwala, M. M. et al. Loss of prolyl hydroxylase-1 protects against colitis through reduced epithelial cell apoptosis and increased barrier function. Gastroenterology 139, 2093–2101 (2010).

    Article  CAS  PubMed  Google Scholar 

  125. Chen, Y. et al. PHD3 stabilizes the tight junction protein occludin and protects intestinal epithelial barrier function. J. Biol. Chem. 290, 20580–20589 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Kalucka, J. et al. Loss of epithelial hypoxia-inducible factor prolyl hydroxylase 2 accelerates skin wound healing in mice. Mol. Cell. Biol. 33, 3426–3438 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Fang, Y., Zhang, H., Zhong, Y. & Ding, X. Prolyl hydroxylase 2 (PHD2) inhibition protects human renal epithelial cells and mice kidney from hypoxia injury. Oncotarget 7, 54317–54328 (2016).

    PubMed  PubMed Central  Google Scholar 

  128. Takeda, K. & Fong, G. H. Prolyl hydroxylase domain 2 protein suppresses hypoxia-induced endothelial cell proliferation. Hypertension 49, 178–184 (2007).

    Article  CAS  PubMed  Google Scholar 

  129. Mazzone, M. et al. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 136, 839–851 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Leite de Oliveira, R. et al. Gene-targeting of Phd2 improves tumor response to chemotherapy and prevents side-toxicity. Cancer Cell 22, 263–277 (2012).

    Article  CAS  PubMed  Google Scholar 

  131. Dai, Z., Li, M., Wharton, J., Zhu, M. M. & Zhao, Y. Y. Prolyl-4 hydroxylase 2 (PHD2) deficiency in endothelial cells and hematopoietic cells induces obliterative vascular remodeling and severe pulmonary arterial hypertension in mice and humans through hypoxia-inducible factor-2α. Circulation 133, 2447–2458 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Kapitsinou, P. P. et al. Theendothelial prolyl-4-hydroxylase domain 2/hypoxia-inducible factor 2 axis regulates pulmonary artery pressure in mice. Mol. Cell. Biol. 36, 1584–1594 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Wang, S. et al. Loss of prolyl hydroxylase domain protein 2 in vascular endothelium increases pericyte coverage and promotes pulmonary arterial remodeling. Oncotarget 7, 58848–58861 (2016).

    PubMed  PubMed Central  Google Scholar 

  134. Wang, S. et al. Ablation of endothelial prolyl hydroxylase domain protein-2 promotes renal vascular remodelling and fibrosis in mice. J. Cell. Mol. Med. http://dx.doi.org/10.1111/jcmm.13117 (2017).

  135. Van Welden, S. et al. Haematopoietic prolyl hydroxylase-1 deficiency promotes M2 macrophage polarization and is both necessary and sufficient to protect against experimental colitis. J. Pathol. 241, 547–558 (2016).

    Article  CAS  Google Scholar 

  136. Wu, S. et al. Enhancement of angiogenesis through stabilization of hypoxia-inducible factor-1 by silencing prolyl hydroxylase domain-2 gene. Mol. Ther. 16, 1227–1234 (2008).

    Article  CAS  PubMed  Google Scholar 

  137. Manresa, M. C. et al. Hydroxylases regulate intestinal fibrosis through the suppression of ERK mediated TGF-β1 signaling. Am. J. Physiol. Gastrointest. Liver Physiol. 311, G1076–G1090 (2016).

    Article  PubMed  Google Scholar 

  138. Walmsley, S. R. et al. Prolyl hydroxylase 3 (PHD3) is essential for hypoxic regulation of neutrophilic inflammation in humans and mice. J. Clin. Invest. 121, 1053–1063 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Takeda, K. et al. Inhibition of prolyl hydroxylase domain-containing protein suppressed lipopolysaccharide-induced TNF-α expression. Arterioscler. Thromb. Vasc. Biol. 29, 2132–2137 (2009).

    Article  CAS  PubMed  Google Scholar 

  140. Ikeda, J. et al. Deletion of Phd2 in myeloid lineage attenuates hypertensive cardiovascular remodeling. J. Am. Heart Assoc. 2, e000178 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Guentsch, A. et al. PHD2 is a regulator for glycolytic reprogramming in macrophages. Mol. Cell. Biol. 37, e00236-16 (2017).

    Article  PubMed  Google Scholar 

  142. Escribese, M. M. et al. The prolyl hydroxylase PHD3 identifies proinflammatory macrophages and its expression is regulated by activin A. J. Immunol. 189, 1946–1954 (2012).

    Article  CAS  PubMed  Google Scholar 

  143. Kiss, J. et al. Loss of the oxygen sensor PHD3 enhances the innate immune response to abdominal sepsis. J. Immunol. 189, 1955–1965 (2012).

    Article  CAS  PubMed  Google Scholar 

  144. Swain, L. et al. Prolyl-4-hydroxylase domain 3 (PHD3) is a critical terminator for cell survival of macrophages under stress conditions. J. Leukoc. Biol. 96, 365–375 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Mamlouk, S. et al. Loss of prolyl hydroxylase-2 in myeloid cells and T-lymphocytes impairs tumor development. Int. J. Cancer 134, 849–858 (2014).

    Article  CAS  PubMed  Google Scholar 

  146. Singh, Y. et al. Prolyl hydroxylase 3 (PHD3) expression augments the development of regulatory T cells. Mol. Immunol. 76, 7–12 (2016).

    Article  CAS  PubMed  Google Scholar 

  147. Clever, D. et al. Oxygen sensing by T cells establishes an immunologically tolerant metastatic niche. Cell 166, 1117–1131.e14 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. 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 

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

    Article  CAS  PubMed  Google Scholar 

  150. Fraisl, P., Aragones, J. & Carmeliet, P. Inhibition of oxygen sensors as a therapeutic strategy for ischaemic and inflammatory disease. Nat. Rev. Drug Discov. 8, 139–152 (2009).

    Article  CAS  PubMed  Google Scholar 

  151. Keely, S. et al. Contribution of epithelial innate immunity to systemic protection afforded by prolyl hydroxylase inhibition in murine colitis. Mucosal. Immunol. 7, 114–123 (2014).

    Article  CAS  PubMed  Google Scholar 

  152. Marks, E. et al. Oral delivery of prolyl hydroxylase inhibitor: AKB-4924 promotes localized mucosal healing in a mouse model of colitis. Inflamm. Bowel. Dis. 21, 267–275 (2015).

    Article  PubMed  Google Scholar 

  153. Gupta, R. et al. Therapeutic treatment with a novel hypoxia-inducible factor hydroxylase inhibitor (TRC160334) ameliorates murine colitis. Clin. Exp. Gastroenterol. 7, 13–23 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Jamadarkhana, P. et al. Treatment with a novel hypoxia-inducible factor hydroxylase inhibitor (TRC160334) ameliorates ischemic acute kidney injury. Am. J. Nephrol. 36, 208–218 (2012).

    Article  CAS  PubMed  Google Scholar 

  155. Jeong, S. et al. Lipophilic modification enhances anti-colitic properties of rosmarinic acid by potentiating its HIF-prolyl hydroxylases inhibitory activity. Eur. J. Pharmacol. 747, 114–122 (2015).

    Article  CAS  PubMed  Google Scholar 

  156. Hart, M. L. et al. Hypoxia-inducible factor-1α-dependent protection from intestinal ischemia/reperfusion injury involves ecto-5′-nucleotidase (CD73) and the A2B adenosine receptor. J. Immunol. 186, 4367–4374 (2011).

    Article  CAS  PubMed  Google Scholar 

  157. Taniguchi, C. M. et al. PHD inhibition mitigates and protects against radiation-induced gastrointestinal toxicity via HIF2. Sci. Transl Med. 6, 236ra64 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Hirota, S. A. et al. Hypoxia-inducible factor signaling provides protection in Clostridium difficile-induced intestinal injury. Gastroenterology 139, 259–269.e3 (2010).

    Article  CAS  PubMed  Google Scholar 

  159. Pergola, P. E., Spinowitz, B. S., Hartman, C. S., Maroni, B. J. & Haase, V. H. Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease. Kidney Int. 90, 1115–1122 (2016).

    Article  CAS  PubMed  Google Scholar 

  160. Provenzano, R. et al. Oral hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) for the treatment of anemia in patients with CKD. Clin. J. Am. Soc. Nephrol. 11, 982–991 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Brigandi, R. A. et al. A novel hypoxia-inducible factor-prolyl hydroxylase inhibitor (GSK1278863) for anemia in CKD: A 28-day, phase 2A randomized trial. Am. J. Kidney Dis. 67, 861–871 (2016).

    Article  CAS  PubMed  Google Scholar 

  162. Roda, J. M. et al. Stabilization of HIF-2α induces sVEGFR-1 production from tumor-associated macrophages and decreases tumor growth in a murine melanoma model. J. Immunol. 189, 3168–3177 (2012).

    Article  CAS  PubMed  Google Scholar 

  163. Shibaji, T. et al. Prognostic significance of HIF-1α overexpression in human pancreatic cancer. Anticancer Res. 23, 4721–4727 (2003).

    CAS  PubMed  Google Scholar 

  164. Yoshimura, H. et al. Prognostic impact of hypoxia-inducible factors 1α and 2α in colorectal cancer patients: correlation with tumor angiogenesis and cyclooxygenase-2 expression. Clin. Cancer Res. 10, 8554–8560 (2004).

    Article  CAS  PubMed  Google Scholar 

  165. Allard, B., Beavis, P. A., Darcy, P. K. & Stagg, J. Immunosuppressive activities of adenosine in cancer. Curr. Opin. Pharmacol. 29, 7–16 (2016).

    Article  CAS  PubMed  Google Scholar 

  166. Antonioli, L., Yegutkin, G. G., Pacher, P., Blandizzi, C. & Hasko, G. Anti-CD73 in cancer immunotherapy: awakening new opportunities. Trends Cancer 2, 95–109 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Stagg, J. et al. Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis. Proc. Natl Acad. Sci. USA 107, 1547–1552 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  168. Ohta, A. et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc. Natl Acad. Sci. USA 103, 13132–13137 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Allard, B., Pommey, S., Smyth, M. J. & Stagg, J. Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clin. Cancer Res. 19, 5626–5635 (2013).

    Article  CAS  PubMed  Google Scholar 

  170. Beavis, P. A. et al. Adenosine receptor 2A blockade increases the efficacy of anti-PD-1 through enhanced antitumor T-cell responses. Cancer Immunol. Res. 3, 506–517 (2015).

    Article  CAS  PubMed  Google Scholar 

  171. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02503774 (2017).

  172. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02403193 (2017).

  173. Xue, X. et al. Hypoxia-inducible factor-2α activation promotes colorectal cancer progression by dysregulating iron homeostasis. Cancer Res. 72, 2285–2293 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Yeo, E. J. et al. YC-1: a potential anticancer drug targeting hypoxia-inducible factor 1. J. Natl Cancer Inst. 95, 516–525 (2003).

    Article  CAS  PubMed  Google Scholar 

  175. Shin, D. H. et al. Preclinical evaluation of YC-1, a HIF inhibitor, for the prevention of tumor spreading. Cancer Lett. 255, 107–116 (2007).

    Article  CAS  PubMed  Google Scholar 

  176. Xue, X., Ramakrishnan, S. K. & Shah, Y. M. Activation of HIF-1α does not increase intestinal tumorigenesis. Am. J. Physiol. Gastrointest. Liver Physiol. 307, G187–G195 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Waldner, M. J. & Neurath, M. F. Colitis-associated cancer: the role of T cells in tumor development. Semin. Immunopathol. 31, 249–256 (2009).

    Article  CAS  PubMed  Google Scholar 

  178. Beaugerie, L. et al. Risk of colorectal high-grade dysplasia and cancer in a prospective observational cohort of patients with inflammatory bowel disease. Gastroenterology 145, 166–178 (2013).

    Article  PubMed  Google Scholar 

  179. Filmann, N. et al. Prevalence of anemia in inflammatory bowel diseases in european countries: a systematic review and individual patient data meta-analysis. Inflamm. Bowel Dis. 20, 936–945 (2014).

    Article  PubMed  Google Scholar 

  180. Kulnigg-Dabsch, S., Evstatiev, R., Dejaco, C. & Gasche, C. Effect of iron therapy on platelet counts in patients with inflammatory bowel disease-associated anemia. PLoS ONE 7, e34520 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Kulnigg-Dabsch, S. et al. Iron deficiency generates secondary thrombocytosis and platelet activation in IBD: the randomized, controlled thromboVIT trial. Inflamm. Bowel Dis. 19, 1609–1616 (2013).

    Article  PubMed  Google Scholar 

  182. Yoshida, H. & Granger, D. N. Inflammatory bowel disease: a paradigm for the link between coagulation and inflammation. Inflamm. Bowel Dis. 15, 1245–1255 (2009).

    Article  PubMed  Google Scholar 

  183. Dhillon, A. P. et al. Mucosal capillary thrombi in rectal biopsies. Histopathology 21, 127–133 (1992).

    Article  CAS  PubMed  Google Scholar 

  184. Miehsler, W. et al. Is inflammatory bowel disease an independent and disease specific risk factor for thromboembolism? Gut 53, 542–548 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Higgins, D. F. et al. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J. Clin. Invest. 117, 3810–3820 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Moon, J. O., Welch, T. P., Gonzalez, F. J. & Copple, B. L. Reduced liver fibrosis in hypoxia-inducible factor-1α-deficient mice. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G582–G592 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Roychowdhury, S., Chiang, D. J., McMullen, M. R. & Nagy, L. E. Moderate, chronic ethanol feeding exacerbates carbon-tetrachloride-induced hepatic fibrosis via hepatocyte-specific hypoxia inducible factor 1α. Pharmacol. Res. Perspect. 2, e00061 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Copple, B. L., Kaska, S. & Wentling, C. Hypoxia-inducible factor activation in myeloid cells contributes to the development of liver fibrosis in cholestatic mice. J. Pharmacol. Exp. Ther. 341, 307–316 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Cosnes, J. et al. Long-term evolution of disease behavior of Crohn's disease. Inflamm. Bowel Dis. 8, 244–250 (2002).

    Article  PubMed  Google Scholar 

  190. Okumura, C. Y. et al. A new pharmacological agent (AKB-4924) stabilizes hypoxia inducible factor-1 (HIF-1) and increases skin innate defenses against bacterial infection. J. Mol. Med. (Berl.) 90, 1079–1089 (2012).

    Article  CAS  Google Scholar 

  191. McDonough, M. A., Loenarz, C., Chowdhury, R., Clifton, I. J. & Schofield, C. J. Structural studies on human 2-oxoglutarate dependent oxygenases. Curr. Opin. Struct. Biol. 20, 659–672 (2010).

    Article  CAS  PubMed  Google Scholar 

  192. Loenarz, C. & Schofield, C. J. Physiological and biochemical aspects of hydroxylations and demethylations catalyzed by human 2-oxoglutarate oxygenases. Trends Biochem. Sci. 36, 7–18 (2011).

    Article  CAS  PubMed  Google Scholar 

  193. Yoon, Y. S., Cho, H., Lee, J. H. & Yoon, G. Mitochondrial dysfunction via disruption of complex II activity during iron chelation-induced senescence-like growth arrest of Chang cells. Ann. NY Acad. Sci. 1011, 123–132 (2004).

    Article  CAS  PubMed  Google Scholar 

  194. Needleman, P., Turk, J., Jakschik, B. A., Morrison, A. R. & Lefkowith, J. B. Arachidonic acid metabolism. Annu. Rev. Biochem. 55, 69–102 (1986).

    Article  CAS  PubMed  Google Scholar 

  195. Tambuwala, M. M. et al. Targeted delivery of the hydroxylase inhibitor DMOG provides enhanced efficacy with reduced systemic exposure in a murine model of colitis. J. Control Release 217, 221–227 (2015).

    Article  CAS  PubMed  Google Scholar 

  196. Van Welden, S., Laukens, D., Ferdinande, L., De, V. M. & Hindryckx, P. Differential expression of prolyl hydroxylase 1 in patients with ulcerative colitis versus patients with Crohn's disease/infectious colitis and healthy controls. J. Inflamm. (Lond.) 10, 36 (2013).

    Article  CAS  Google Scholar 

  197. Quaegebeur, A. et al. Deletion or inhibition of the oxygen sensor PHD1 protects against ischemic stroke via reprogramming of neuronal metabolism. Cell Metab. 23, 280–291 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Nguyen, L. K. et al. A dynamic model of the hypoxia-inducible factor 1α (HIF-1α) network. J. Cell Sci. 126, 1454–1463 (2013).

    Article  CAS  PubMed  Google Scholar 

  199. Scholz, C. C. et al. Regulation of IL-1β-induced NF-κB by hydroxylases links key hypoxic and inflammatory signaling pathways. Proc. Natl Acad. Sci. USA 110, 18490–18495 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Arai, Y., Takanashi, H., Kitagawa, H. & Okayasu, I. Involvement of interleukin-1 in the development of ulcerative colitis induced by dextran sulfate sodium in mice. Cytokine 10, 890–896 (1998).

    Article  CAS  PubMed  Google Scholar 

  201. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02892149 (2017).

  202. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02865850 (2017).

  203. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02680574 (2017).

  204. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02648347 (2017).

  205. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02876835 (2017).

  206. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02879305 (2017).

  207. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02969655 (2017).

  208. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02914262 (2017).

  209. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01750190 (2017).

  210. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02021318 (2016).

  211. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02174627 (2017).

  212. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02652806 (2017).

  213. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02652819 (2017).

  214. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02273726 (2017).

  215. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01887600 (2017).

  216. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02055482 (2017).

  217. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01975818 (2016).

  218. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02064426 (2017).

Download references

Acknowledgements

The authors are supported by a research grant from the Research Foundation of Flanders (FWO, G075312) and a concerted grant of the Special Research Fund (BOF; GOA 2012/01G00812 and GOA 2017000902) of Ghent University, Belgium.

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Ghent University, De Pintelaan 185, 1K12-E, Ghent, 9000, Belgium

    Sophie Van Welden & Pieter Hindryckx

  2. Robarts Clinical Trials West, 4350 Executive Drive 210, San Diego, 92121, California, USA

    Andrew C. Selfridge

Authors
  1. Sophie Van Welden
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew C. Selfridge
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pieter Hindryckx
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

P.H. and S.V.W. researched data for the article. All of the authors contributed to discussion of content for the manuscript. P.H. and S.V.W. wrote the article, and P.H. and A.S. reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Pieter Hindryckx.

Ethics declarations

Competing interests

P.H. has received consultancy fees from Abbvie, Ferring and Takeda, honoraria for speaking from Abbvie, Chiesi, Falk Pharma, Ferring, Takeda and Vifor Pharma, and an investigator-initiated study grant from Takeda. S.V.W. and A.S. declare no competing interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Van Welden, S., Selfridge, A. & Hindryckx, P. Intestinal hypoxia and hypoxia-induced signalling as therapeutic targets for IBD. Nat Rev Gastroenterol Hepatol 14, 596–611 (2017). https://doi.org/10.1038/nrgastro.2017.101

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrgastro.2017.101

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