The role of hypoxia in intestinal inflammation
© Shah. 2016
Received: 30 November 2015
Accepted: 5 January 2016
Published: 26 January 2016
Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease of the intestine. IBD is a multifactorial disorder, and IBD-associated genes are critical in innate immune response, inflammatory response, autophagy, and epithelial barrier integrity. Moreover, epithelial oxygen tension plays a critical role in intestinal inflammation and resolution in IBD. The intestines have a dynamic and rapid fluctuation in cellular oxygen tension, which is dysregulated in IBD. Intestinal epithelial cells have a steep oxygen gradient where the tips of the villi are hypoxic and the oxygenation increases at the base of the villi. IBD results in heightened hypoxia throughout the mucosa. Hypoxia signals through a well-conserved family of transcription factors, where hypoxia-inducible factor (HIF)-1α and HIF-2α are essential in maintaining intestinal homeostasis. In inflamed mucosa, HIF-1α increases barrier protective genes, elicits protective innate immune responses, and activates an antimicrobial response through the increase in β-defensins. HIF-2α is essential in maintaining an epithelial-elicited inflammatory response and the regenerative and proliferative capacity of the intestine following an acute injury. HIF-1α activation in colitis leads to a protective response, whereas chronic activation of HIF-2α increases the pro-inflammatory response, intestinal injury, and cancer. In this mini-review, we detail the role of HIF-1α and HIF-2α in intestinal inflammation and injury and therapeutic implications of targeting HIF signaling in IBD.
The intestine is a highly regenerative tissue, which completely renews every 5 to 6 days. The intestinal epithelial cells are critical for digestion, secretion of hormones and mucin, and absorption of nutrients. The epithelial cells are under control by an exquisite signaling cascade (Notch, BMP, Wnt/β-catenin) that maintains proliferation and differentiation of epithelial progenitors and the self-renewal capacity of intestinal epithelial stem cells. In addition, cellular oxygen dynamics are critical in maintaining intestinal homeostasis. The intricate oxygen gradient in the intestine is set up by the rapid propagation of the enteric microbiota just after birth. The microbiota composition of newborns suggests that aerobic and facultative anaerobic bacteria consume luminal oxygen, which allows the growth of obligate anaerobes and establishes an anoxic lumen . The anoxic lumen in part establishes the oxygen gradient of the intestinal epithelium, as cells directly adjacent to the lumen are hypoxic relative to the cells that are close to the base of the crypts . Moreover, microbiota-derived short-chain fatty acids regulate oxygen consumption in intestinal epithelial cells . Dysregulation of oxygen gradients is observed in inflammatory bowel disease (IBD). IBD is divided into two major subgroups: ulcerative colitis (UC) and Crohn’s disease (CD). The precise etiology of IBD is unknown. However, oxygen signaling plays an important function in the inflammatory and injury response.
Oxygen sensing and signaling in the intestine
Hypoxia and IBD
Using staining techniques to visualize hypoxic foci, a robust increase in hypoxia is observed in mouse models of colitis . Physiological hypoxia as mentioned above is localized to epithelial cells adjacent to the lumen. In colitis, hypoxic staining is observed throughout the mucosa. The precise mechanism for the increase in hypoxia is not clear, but it is likely due to several factors. Inflammation leads to enhanced oxygen consumption of intestinal epithelial cells. Inflammation increases local vasculitis and thus decreasing the oxygen availability to inflamed areas . Recently, it was shown that transmigrating neutrophils can consume local oxygen, thereby enhancing hypoxia in colitis . In addition to hypoxic staining in mouse models, HIF-1α and HIF-2α are highly increased in epithelial cells in UC and CD patients . Currently, the expression and function of HIF-3α have not been thoroughly assessed.
HIF-1α and HIF-2α targets in IBD
Currently, the pan-PHD inhibitors dimethyloxaloylglycine, FG-4497, and TRC160334 are protective in mouse models of colitis [14, 15, 22]. However, HIF-2α may increase the inflammatory response, and therefore, optimal HIF-based therapies would be pharmacological agents that can specifically increase HIF-1α. AKB-4924 is a PHD inhibitor that results in modest activation of HIF-2α but robustly activates HIF-1α . AKB-4924 increases the antimicrobial response and protective innate immune response. AKB-4924 treatment improves the intestinal barrier integrity and reduces the pro-inflammatory response. The beneficial effects of AKB-4924 were due to intestinal HIF-1α, as disruption of HIF-1α attenuated the protective role . Moreover, HIF-2α inhibitors have been recently identified. HIF-2α (but not HIF-1α) contains ligand-binding cavity, although endogenous substrates have not been identified . This cavity has been targeted for drug development, and several promising highly specific small-molecule inhibitors are identified . Currently, these drugs have not been assessed in mouse models of colitis, but the data suggest that disruption of intestinal epithelial HIF-2α decreases the inflammatory response in colitis .
HIF-1α and HIF-2α play an essential role in IBD. Understanding the temporal regulation of HIF-1α and HIF-2α will be key to design novel and effective HIF-based therapies for IBD. It is likely that both responses are critical in the initiation and resolution of intestinal inflammation. HIF-1α increases the barrier integrity and antimicrobial response, whereas HIF-2α activates pro-inflammatory mediators to elicit an immune response and stimulates epithelial proliferation to promote regeneration. However, more work is needed to understand the dynamic regulation of HIF-1α and HIF-2α in models of chronic colitis.
This work was supported by NIH grants: CA148828 and DK095201, to YMS.
The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
- Albenberg L, Esipova TV, Judge CP, Bittinger K, Chen J, Laughlin A, Grunberg S, Baldassano RN, Lewis JD, Li H, Thom SR, Bushman FD, Vinogradov SA, Wu GD (2014) Correlation between intraluminal oxygen gradient and radial partitioning of intestinal microbiota. Gastroenterology 147(5):1055–1063 e1058. doi:10.1053/j.gastro.2014.07.020 View ArticlePubMedPubMed CentralGoogle Scholar
- Karhausen J, Furuta GT, Tomaszewski JE, Johnson RS, Colgan SP, Haase VH (2004) Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis. J Clin Invest 114(8):1098–1106. doi:10.1172/JCI21086 View ArticlePubMedPubMed CentralGoogle Scholar
- Kelly CJ, Zheng L, Campbell EL, Saeedi B, Scholz CC, Bayless AJ, Wilson KE, Glover LE, Kominsky DJ, Magnuson A, Weir TL, Ehrentraut SF, Pickel C, Kuhn KA, Lanis JM, Nguyen V, Taylor CT, Colgan SP (2015) Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function. Cell Host Microbe 17(5):662–671. doi:10.1016/j.chom.2015.03.005 View ArticlePubMedPubMed CentralGoogle Scholar
- Taniguchi CM, Miao YR, Diep AN, Wu C, Rankin EB, Atwood TF, Xing L, Giaccia AJ (2014) PHD inhibition mitigates and protects against radiation-induced gastrointestinal toxicity via HIF2. Sci Transl Med 6 (236):236ra264. doi:10.1126/scitranslmed.3008523
- Schodel J, Mole DR, Ratcliffe PJ (2013) Pan-genomic binding of hypoxia-inducible transcription factors. Biol Chem 394(4):507–517. doi:10.1515/hsz-2012-0351 View ArticlePubMedGoogle Scholar
- Colgan SP, Taylor CT (2010) Hypoxia: an alarm signal during intestinal inflammation. Nat Rev Gastroenterol Hepatol 7(5):281–287. doi:10.1038/nrgastro.2010.39 View ArticlePubMedPubMed CentralGoogle Scholar
- Campbell EL, Bruyninckx WJ, Kelly CJ, Glover LE, McNamee EN, Bowers BE, Bayless AJ, Scully M, Saeedi BJ, Golden-Mason L, Ehrentraut SF, Curtis VF, Burgess A, Garvey JF, Sorensen A, Nemenoff R, Jedlicka P, Taylor CT, Kominsky DJ, Colgan SP (2014) Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation. Immunity 40(1):66–77. doi:10.1016/j.immuni.2013.11.020 View ArticlePubMedPubMed CentralGoogle Scholar
- Xue X, Ramakrishnan S, Anderson E, Taylor M, Zimmermann EM, Spence JR, Huang S, Greenson JK, Shah YM (2013) Endothelial PAS domain protein 1 activates the inflammatory response in the intestinal epithelium to promote colitis in mice. Gastroenterology 145(4):831–841. doi:10.1053/j.gastro.2013.07.010 View ArticlePubMedPubMed CentralGoogle Scholar
- Furuta GT, Turner JR, Taylor CT, Hershberg RM, Comerford K, Narravula S, Podolsky DK, Colgan SP (2001) Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia. J Exp Med 193(9):1027–1034View ArticlePubMedPubMed CentralGoogle Scholar
- Louis NA, Hamilton KE, Canny G, Shekels LL, Ho SB, Colgan SP (2006) Selective induction of mucin-3 by hypoxia in intestinal epithelia. J Cell Biochem 99(6):1616–1627. doi:10.1002/jcb.20947 View ArticlePubMedGoogle Scholar
- Synnestvedt K, Furuta GT, Comerford KM, Louis N, Karhausen J, Eltzschig HK, Hansen KR, Thompson LF, Colgan SP (2002) Ecto-5′-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia. J Clin Invest 110(7):993–1002. doi:10.1172/JCI15337 View ArticlePubMedPubMed CentralGoogle Scholar
- Keely S, Campbell EL, Baird AW, Hansbro PM, Shalwitz RA, Kotsakis A, McNamee EN, Eltzschig HK, Kominsky DJ, Colgan SP (2014) Contribution of epithelial innate immunity to systemic protection afforded by prolyl hydroxylase inhibition in murine colitis. Mucosal Immunol 7(1):114–123. doi:10.1038/mi.2013.29 View ArticlePubMedGoogle Scholar
- Kelly CJ, Glover LE, Campbell EL, Kominsky DJ, Ehrentraut SF, Bowers BE, Bayless AJ, Saeedi BJ, Colgan SP (2013) Fundamental role for HIF-1alpha in constitutive expression of human beta defensin-1. Mucosal Immunol 6(6):1110–1118. doi:10.1038/mi.2013.6 PubMedPubMed CentralGoogle Scholar
- Cummins EP, Seeballuck F, Keely SJ, Mangan NE, Callanan JJ, Fallon PG, Taylor CT (2008) The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis. Gastroenterology 134(1):156–165. doi:10.1053/j.gastro.2007.10.012 View ArticlePubMedGoogle Scholar
- Robinson A, Keely S, Karhausen J, Gerich ME, Furuta GT, Colgan SP (2008) Mucosal protection by hypoxia-inducible factor prolyl hydroxylase inhibition. Gastroenterology 134(1):145–155. doi:10.1053/j.gastro.2007.09.033 View ArticlePubMedPubMed CentralGoogle Scholar
- Glover LE, Bowers BE, Saeedi B, Ehrentraut SF, Campbell EL, Bayless AJ, Dobrinskikh E, Kendrick AA, Kelly CJ, Burgess A, Miller L, Kominsky DJ, Jedlicka P, Colgan SP (2013) Control of creatine metabolism by HIF is an endogenous mechanism of barrier regulation in colitis. Proc Natl Acad Sci U S A 110(49):19820–19825. doi:10.1073/pnas.1302840110 View ArticlePubMedPubMed CentralGoogle Scholar
- Xie L, Xue X, Taylor M, Ramakrishnan SK, Nagaoka K, Hao C, Gonzalez FJ, Shah YM (2014) 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(16):3013–3023. doi:10.1128/MCB.00324-14 View ArticlePubMedPubMed CentralGoogle Scholar
- Xue X, Ramakrishnan SK, Shah YM (2014) Activation of HIF-1alpha does not increase intestinal tumorigenesis. Am J Physiol Gastrointest Liver Physiol 307(2):G187–G195. doi:10.1152/ajpgi.00112.2014 View ArticlePubMedPubMed CentralGoogle Scholar
- Xue X, Taylor M, Anderson E, Hao C, Qu A, Greenson JK, Zimmermann EM, Gonzalez FJ, Shah YM (2012) Hypoxia-inducible factor-2alpha activation promotes colorectal cancer progression by dysregulating iron homeostasis. Cancer Res 72(9):2285–2293. doi:10.1158/0008-5472.CAN-11-3836 View ArticlePubMedPubMed CentralGoogle Scholar
- Xue X, Shah YM (2013) Hypoxia-inducible factor-2alpha is essential in activating the COX2/mPGES-1/PGE2 signaling axis in colon cancer. Carcinogenesis 34(1):163–169. doi:10.1093/carcin/bgs313 View ArticlePubMedGoogle Scholar
- Bruning U, Cerone L, Neufeld Z, Fitzpatrick SF, Cheong A, Scholz CC, Simpson DA, Leonard MO, Tambuwala MM, Cummins EP, Taylor CT (2011) MicroRNA-155 promotes resolution of hypoxia-inducible factor 1alpha activity during prolonged hypoxia. Mol Cell Biol 31(19):4087–4096. doi:10.1128/MCB.01276-10 View ArticlePubMedPubMed CentralGoogle Scholar
- Gupta R, Chaudhary AR, Shah BN, Jadhav AV, Zambad SP, Gupta RC, Deshpande S, Chauthaiwale V, Dutt C (2014) Therapeutic treatment with a novel hypoxia-inducible factor hydroxylase inhibitor (TRC160334) ameliorates murine colitis. Clin Exper Gastroenterol 7:13–23. doi:10.2147/CEG.S51923 View ArticleGoogle Scholar
- Okumura CY, Hollands A, Tran DN, Olson J, Dahesh S, von Kockritz-Blickwede M, Thienphrapa W, Corle C, Jeung SN, Kotsakis A, Shalwitz RA, Johnson RS, Nizet V (2012) A new pharmacological agent (AKB-4924) stabilizes hypoxia inducible factor-1 (HIF-1) and increases skin innate defenses against bacterial infection. J Mol Med 90(9):1079–1089. doi:10.1007/s00109-012-0882-3 View ArticlePubMedPubMed CentralGoogle Scholar
- Wu D, Potluri N, Lu J, Kim Y, Rastinejad F (2015) Structural integration in hypoxia-inducible factors. Nature 524(7565):303–308. doi:10.1038/nature14883 View ArticlePubMedGoogle Scholar
- Scheuermann TH, Li Q, Ma HW, Key J, Zhang L, Chen R, Garcia JA, Naidoo J, Longgood J, Frantz DE, Tambar UK, Gardner KH, Bruick RK (2013) Allosteric inhibition of hypoxia inducible factor-2 with small molecules. Nat Chem Biol 9(4):271–276. doi:10.1038/nchembio.1185 View ArticlePubMedPubMed CentralGoogle Scholar