Sites of inflammation are defined by significant changes in metabolic activity. Recent studies have suggested that O metabolism and hypoxia play a prominent role in inflammation so-called “inflammatory hypoxia,” which results from a combination of recruited inflammatory cells (e.g., neutrophils and monocytes), the local proliferation of multiple cell types, and the activation of multiple O-consuming enzymes during inflammation. These shifts in energy supply and demand result in localized regions of hypoxia and have revealed the important function off the transcription factor HIF (hypoxia-inducible factor) in the regulation of key target genes that promote inflammatory resolution. Analysis of these pathways has provided multiple opportunities for understanding basic mechanisms of inflammation and has defined new targets for intervention. Here, we review recent work addressing tissue hypoxia and metabolic control of inflammation and immunity.


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Literature Cited

  1. Kominsky DJ, Campbell EL, Colgan SP. 1.  2010. Metabolic shifts in immunity and inflammation. J. Immunol. 184:4062–68 [Google Scholar]
  2. Colgan SP, Taylor CT. 2.  2010. Hypoxia: an alarm signal during intestinal inflammation. Nat. Rev. Gastroenterol. Hepatol. 7:281–87 [Google Scholar]
  3. Lewis JS, Lee JA, Underwood JC, Harris AL, Lewis CE. 3.  1999. Macrophage responses to hypoxia: relevance to disease mechanisms. J. Leukoc. Biol. 66:889–900 [Google Scholar]
  4. Fox CJ, Hammerman PS, Thompson CB. 4.  2005. Fuel feeds function: energy metabolism and the T-cell response. Nat. Rev. Immunol. 5:844–52 [Google Scholar]
  5. Sitkovsky M, Lukashev D. 5.  2005. Regulation of immune cells by local-tissue oxygen tension: HIF1α and adenosine receptors. Nat. Rev. Immunol. 5:712–21 [Google Scholar]
  6. Shepherd AP. 6.  1982. Metabolic control of intestinal oxygenation and blood flow. Fed. Proc. 41:2084–89 [Google Scholar]
  7. Albenberg L, Esipova TV, Judge CP, Bittinger K, Chen J. 7.  et al. 2014. Correlation between intraluminal oxygen gradient and radial partitioning of intestinal microbiota. Gastroenterology 18:1055–63 [Google Scholar]
  8. Schaible B, Schaffer K, Taylor CT. 8.  2010. Hypoxia, innate immunity and infection in the lung. Respir. Physiol. Neurobiol. 174:235–43 [Google Scholar]
  9. Karhausen J, Furuta GT, Tomaszewski JE, Johnson RS, Colgan SP, Haase VH. 9.  2004. Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis. J. Clin. Investig. 114:1098–106 [Google Scholar]
  10. Evans SM, Hahn S, Pook DR, Jenkins WT, Chalian AA. 10.  et al. 2000. Detection of hypoxia in human squamous cell carcinoma by EF5 binding. Cancer Res. 60:2018–24 [Google Scholar]
  11. Kelly CJ, Glover LE, Campbell EL, Kominsky DJ, Ehrentraut SF. 11.  et al. 2013. Fundamental role for HIF-1α in constitutive expression of human β defensin-1. Mucosal Immunol. 6:1110–18 [Google Scholar]
  12. Takasawa M, Moustafa RR, Baron JC. 12.  2008. Applications of nitroimidazole in vivo hypoxia imaging in ischemic stroke. Stroke 39:1629–37 [Google Scholar]
  13. Kizaka-Kondoh S, Konse-Nagasawa H. 13.  2009. Significance of nitroimidazole compounds and hypoxia-inducible factor-1 for imaging tumor hypoxia. Cancer Sci. 100:1366–73 [Google Scholar]
  14. Guise CP, Mowday AM, Ashoorzadeh A, Yuan R, Lin WH. 14.  et al. 2014. Bioreductive prodrugs as cancer therapeutics: targeting tumor hypoxia. Chin. J. Cancer. 33:80–86 [Google Scholar]
  15. Furuta GT, Turner JR, Taylor CT, Hershberg RM, Comerford K. 15.  et al. 2001. Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia. J. Exp. Med. 193:1027–34 [Google Scholar]
  16. Comerford KM, Wallace TJ, Karhausen J, Louis NA, Montalto MC, Colgan SP. 16.  2002. Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res. 62:3387–94 [Google Scholar]
  17. Synnestvedt K, Furuta GT, Comerford KM, Louis N, Karhausen J. 17.  et al. 2002. Ecto-5′-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia. J. Clin. Investig. 110:993–1002 [Google Scholar]
  18. Eltzschig HK, Ibla JC, Furuta GT, Leonard MO, Jacobson KA. 18.  et al. 2003. Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors. J. Ex. Med. 198:783–96 [Google Scholar]
  19. Semenza GL. 19.  2011. Regulation of metabolism by hypoxia-inducible factor 1. Cold Spring Harb. Symp. Quant. Biol. 2011:22 [Google Scholar]
  20. Semenza GL. 20.  2001. HIF-1, O2, and the 3 PHDs: how animal cells signal hypoxia to the nucleus. Cell 107:1–3 [Google Scholar]
  21. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC. 21.  et al. 1999. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271–75 [Google Scholar]
  22. Tanimoto K, Makino Y, Pereira T, Poellinger L. 22.  2000. Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. EMBO J. 19:4298–309 [Google Scholar]
  23. Lando D, Peet DJ, Whelan DA, Gorman JJ, Murray LW. 23.  2002. Asparagine hydroxylation of the HIF transactivation domain: a hypoxic switch. Science 295:858–61 [Google Scholar]
  24. Karhausen J, Stafford-Smith M. 24.  2014. The role of nonocclusive sources of acute gut injury in cardiac surgery. J. Cardiothorac. Vasc. Anesth. 28:379–91 [Google Scholar]
  25. Colgan SP, Curtis VF, Lanis JM, Glover LE. 25.  2015. Metabolic regulation of intestinal epithelial barrier during inflammation. Tissue Barriers 3:1–2e970936 [Google Scholar]
  26. Pannabecker TL, Layton AT. 26.  2014. Targeted delivery of solutes and oxygen in the renal medulla: role of microvessel architecture. Am. J. Physiol. Ren. Physiol. 307:F649–55 [Google Scholar]
  27. Cummins EP, Seeballuck F, Keely SJ, Mangan NE, Callanan JJ. 27.  et al. 2008. The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis. Gastroenterology 134:156–65 [Google Scholar]
  28. Han IO, Kim HS, Kim HC, Joe EH, Kim WK. 28.  2003. Synergistic expression of inducible nitric oxide synthase by phorbol ester and interferon-γ is mediated through NF-κB and ERK in microglial cells. J. Neurosci. Res. 73:659–69 [Google Scholar]
  29. Morote-Garcia JC, Rosenberger P, Nivillac NM, Coe IR, Eltzschig HK. 29.  2009. Hypoxia-inducible factor-dependent repression of equilibrative nucleoside transporter 2 attenuates mucosal inflammation during intestinal hypoxia. Gastroenterology 136:607–18 [Google Scholar]
  30. Robinson A, Keely S, Karhausen J, Gerich ME, Furuta GT, Colgan SP. 30.  2008. Mucosal protection by hypoxia-inducible factor prolyl hydroxylase inhibition. Gastroenterology 134:145–55 [Google Scholar]
  31. Shah YM, Ito S, Morimura K, Chen C, Yim SH. 31.  et al. 2008. Hypoxia-inducible factor augments experimental colitis through an MIF-dependent inflammatory signaling cascade. Gastroenterology 134:2036–48.e3 [Google Scholar]
  32. Giatromanolaki A, Sivridis E, Maltezos E, Papazoglou D, Simopoulos C. 32.  et al. 2003. Hypoxia inducible factor 1alpha and 2alpha overexpression in inflammatory bowel disease. J. Clin. Pathol. 56:209–13 [Google Scholar]
  33. Mariani F, Sena P, Marzona L, Riccio M, Fano R. 33.  et al. 2009. Cyclooxygenase-2 and Hypoxia-Inducible Factor-1alpha protein expression is related to inflammation, and up-regulated since the early steps of colorectal carcinogenesis. Cancer Lett. 279:221–29 [Google Scholar]
  34. Matthijsen RA, Derikx JP, Kuipers D, van Dam RM, Dejong CH, Buurman WA. 34.  2009. Enterocyte shedding and epithelial lining repair following ischemia of the human small intestine attenuate inflammation. PLOS ONE 4:e7045 [Google Scholar]
  35. Louis NA, Hamilton KE, Canny G, Shekels LL, Ho SB, Colgan SP. 35.  2006. Selective induction of mucin-3 by hypoxia in intestinal epithelia. J. Cell Biochem. 99:1616–27 [Google Scholar]
  36. Furuta GT. 36.  2001. Clinicopathologic features of esophagitis in children. Gastrointest. Endosc. Clin. N. Am. 11:683–715, vii [Google Scholar]
  37. van Raam BJ, Sluiter W, de Wit E, Roos D, Verhoeven AJ, Kuijpers TW. 37.  2008. Mitochondrial membrane potential in human neutrophils is maintained by complex III activity in the absence of supercomplex organisation. PLOS ONE 3:e2013 [Google Scholar]
  38. Pollard TD, Borisy GG. 38.  2003. Cellular motility driven by assembly and disassembly of actin filaments. Cell 112:453–65 [Google Scholar]
  39. Borregaard N, Herlin T. 39.  1982. Energy metabolism of human neutrophils during phagocytosis. J. Clin. Investig. 70:550–57 [Google Scholar]
  40. Greiner EF, Guppy M, Brand K. 40.  1994. Glucose is essential for proliferation and the glycolytic enzyme induction that provokes a transition to glycolytic energy production. J. Biol. Chem. 269:31484–90 [Google Scholar]
  41. Plas DR, Rathmell JC, Thompson CB. 41.  2002. Homeostatic control of lymphocyte survival: potential origins and implications. Nat. Immunol. 3:515–21 [Google Scholar]
  42. Chin AC, Parkos CA. 42.  2007. Pathobiology of neutrophil transepithelial migration: implications in mediating epithelial injury. Annu. Rev. Pathol. Mech. Dis. 2:111–43 [Google Scholar]
  43. Voisin MB, Nourshargh S. 43.  2013. Neutrophil transmigration: emergence of an adhesive cascade within venular walls. J. Innate Immun. 5:336–47 [Google Scholar]
  44. Qi J, Chen N, Wang J, Siu CH. 44.  2005. Transendothelial migration of melanoma cells involves N-cadherin-mediated adhesion and activation of the beta-catenin signaling pathway. Mol. Biol. Cell 16:4386–97 [Google Scholar]
  45. Tickenbrock L, Schwable J, Strey A, Sargin B, Hehn S. 45.  et al. 2006. Wnt signaling regulates transendothelial migration of monocytes. J. Leukoc. Biol. 79:1306–13 [Google Scholar]
  46. Williams MR, Sakurai Y, Zughaier SM, Eskin SG, McIntire LV. 46.  2009. Transmigration across activated endothelium induces transcriptional changes, inhibits apoptosis, and decreases antimicrobial protein expression in human monocytes. J. Leukoc. Biol. 86:1331–43 [Google Scholar]
  47. Williams MR, Kataoka N, Sakurai Y, Powers CM, Eskin SG, McIntire LV. 47.  2008. Gene expression of endothelial cells due to interleukin-1 beta stimulation and neutrophil transmigration. Endothelium 15:73–165 [Google Scholar]
  48. Zemans RL, Briones N, Campbell M, McClendon J, Young SK. 48.  et al. 2011. Neutrophil transmigration triggers repair of the lung epithelium via β-catenin signaling. PNAS 108:15990–95 [Google Scholar]
  49. Campbell EL, Bruyninckx WJ, Kelly CJ, Glover LE, McNamee EN. 49.  et al. 2014. Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation. Immunity 40:66–77 [Google Scholar]
  50. Colgan SP, Dzus AL, Parkos CA. 50.  1996. Epithelial exposure to hypoxia modulates neutrophil transepithelial migration. J. Exp. Med. 184:1003–15 [Google Scholar]
  51. Huang JS, Noack D, Rae J, Ellis BA, Newbury R. 51.  et al. 2004. Chronic granulomatous disease caused by a deficiency in p47phox mimicking Crohn's disease. Clin. Gastroenterol. Hepatol. 2:690–95 [Google Scholar]
  52. Werlin SL, Chusid MJ, Caya J, Oechler HW. 52.  1982. Colitis in chronic granulomatous disease. Gastroenterology 82:328–31 [Google Scholar]
  53. Kaidi A, Williams AC, Paraskeva C. 53.  2007. Interaction between β-catenin and HIF-1 promotes cellular adaptation to hypoxia. Nat. Cell Biol. 9:210–17 [Google Scholar]
  54. Hegazi RA, Rao KN, Mayle A, Sepulveda AR, Otterbein LE, Plevy SE. 54.  2005. Carbon monoxide ameliorates chronic murine colitis through a heme oxygenase 1–dependent pathway. J. Exp. Med. 202:1703–13 [Google Scholar]
  55. Moncada S, Erusalimsky JD. 55.  2002. Does nitric oxide modulate mitochondrial energy generation and apoptosis?. Nat. Rev. Mol. Cell Biol. 3:214–20 [Google Scholar]
  56. Metzen E, Zhou J, Jelkmann W, Fandrey J, Brune B. 56.  2003. Nitric oxide impairs normoxic degradation of HIF-1alpha by inhibition of prolyl hydroxylases. Mol. Biol. Cell 14:3470–81 [Google Scholar]
  57. Hagen T, Taylor CT, Lam F, Moncada S. 57.  2003. Redistribution of intracellular oxygen in hypoxia by nitric oxide: effect on HIF1α. Science 302:1975–78 [Google Scholar]
  58. Jann NJ, Schmaler M, Kristian SA, Radek KA, Gallo RL. 58.  et al. 2009. Neutrophil antimicrobial defense against Staphylococcus aureus is mediated by phagolysosomal but not extracellular trap-associated cathelicidin. J. Leukoc. Biol. 86:1159–69 [Google Scholar]
  59. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y. 59.  et al. 2004. Neutrophil extracellular traps kill bacteria. Science 303:1532–35 [Google Scholar]
  60. Remijsen Q, Kuijpers TW, Wirawan E, Lippens S, Vandenabeele P, Vanden Berghe T. 60.  2011. Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality. Cell Death Differ. 18:581–88 [Google Scholar]
  61. Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I. 61.  et al. 2007. Novel cell death program leads to neutrophil extracellular traps. J. Cell Biol. 176:231–41 [Google Scholar]
  62. Papayannopoulos V, Metzler KD, Hakkim A, Zychlinsky A. 62.  2010. Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J. Cell Biol. 191:677–91 [Google Scholar]
  63. McInturff AM, Cody MJ, Elliott EA, Glenn JW, Rowley JW. 63.  et al. 2012. Mammalian target of rapamycin regulates neutrophil extracellular trap formation via induction of hypoxia-inducible factor 1α. Blood 120:3118–25 [Google Scholar]
  64. McGovern NN, Cowburn AS, Porter L, Walmsley SR, Summers C. 64.  et al. 2011. Hypoxia selectively inhibits respiratory burst activity and killing of Staphylococcus aureus in human neutrophils. J. Immunol. 186:453–63 [Google Scholar]
  65. Stone TW, Darlington LG. 65.  2002. Endogenous kynurenines as targets for drug discovery and development. Nat. Rev. Drug Discov. 1:609–20 [Google Scholar]
  66. Yamamoto S, Hayaishi O. 66.  1967. Tryptophan pyrrolase of rabbit intestine. D- and L-tryptophan-cleaving enzyme or enzymes. J. Biol. Chem. 242:5260–66 [Google Scholar]
  67. Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ. 67.  et al. 1998. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281:1191–93 [Google Scholar]
  68. Keller TL, Zocco D, Sundrud MS, Hendrick M, Edenius M. 68.  et al. 2012. Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. Nat. Chem. Biol. 8:311–17 [Google Scholar]
  69. Sundrud MS, Koralov SB, Feuerer M, Calado DP, Kozhaya AE. 69.  et al. 2009. Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response. Science 324:1334–38 [Google Scholar]
  70. Fallarino F, Grohmann U, You S, McGrath BC, Cavener DR. 70.  et al. 2006. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J. Immunol. 176:6752–61 [Google Scholar]
  71. Sharma MD, Baban B, Chandler P, Hou DY, Singh N. 71.  et al. 2007. Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J. Clin. Investig. 117:2570–82 [Google Scholar]
  72. Pallotta MT, Orabona C, Volpi C, Vacca C, Belladonna ML. 72.  et al. 2011. Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells. Nat. Immunol. 12:870–78 [Google Scholar]
  73. Kazlauskas A, Poellinger L, Pongratz I. 73.  1999. Evidence that the co-chaperone p23 regulates ligand responsiveness of the dioxin (aryl hydrocarbon) receptor. J. Biol. Chem. 274:13519–24 [Google Scholar]
  74. Ma Q, Whitlock JP Jr. 74.  1997. A novel cytoplasmic protein that interacts with the Ah receptor, contains tetratricopeptide repeat motifs, and augments the transcriptional response to 2,3,7,8-tetrachlorodibenzo-p-dioxin. J. Biol. Chem. 272:8878–84 [Google Scholar]
  75. Perdew GH. 75.  1988. Association of the Ah receptor with the 90-kDa heat shock protein. J. Biol. Chem. 263:13802–5 [Google Scholar]
  76. Burbach KM, Poland A, Bradfield CA. 76.  1992. Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor. PNAS 89:8185–89 [Google Scholar]
  77. Schrenk D. 77.  1998. Impact of dioxin-type induction of drug-metabolizing enzymes on the metabolism of endo- and xenobiotics. Biochem. Pharmacol. 55:1155–62 [Google Scholar]
  78. Tomita S, Jiang HB, Ueno T, Takagi S, Tohi K. 78.  et al. 2003. T cell-specific disruption of arylhydrocarbon receptor nuclear translocator (Arnt) gene causes resistance to 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced thymic involution. J. Immunol. 171:4113–20 [Google Scholar]
  79. Mandal PK. 79.  2005. Dioxin: a review of its environmental effects and its aryl hydrocarbon receptor biology. J. Comp. Physiol. B 175:221–30 [Google Scholar]
  80. Fernandez-Salguero P, Pineau T, Hilbert DM, McPhail T, Lee SS. 80.  et al. 1995. Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science 268:722–6 [Google Scholar]
  81. Schmidt JV, Su GH, Reddy JK, Simon MC, Bradfield CA. 81.  1996. Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development. PNAS 93:6731–36 [Google Scholar]
  82. Vogel CF, Goth SR, Dong B, Pessah IN, Matsumura F. 82.  2008. Aryl hydrocarbon receptor signaling mediates expression of indoleamine 2,3-dioxygenase. Biochem. Biophys. Res. Commun. 375:331–35 [Google Scholar]
  83. DiNatale BC, Murray IA, Schroeder JC, Flaveny CA, Lahoti TS. 83.  et al. 2010. Kynurenic acid is a potent endogenous aryl hydrocarbon receptor ligand that synergistically induces interleukin-6 in the presence of inflammatory signaling. Toxicol. Sci. 115:89–97 [Google Scholar]
  84. Rieber N, Belohradsky BH. 84.  2010. AHR activation by tryptophan—pathogenic hallmark of Th17-mediated inflammation in eosinophilic fasciitis, eosinophilia-myalgia-syndrome and toxic oil syndrome?. Immunol. Lett. 128:154–55 [Google Scholar]
  85. Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA. 85.  2010. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J. Immunol. 185:3190–98 [Google Scholar]
  86. Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I. 86.  et al. 2011. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478:197–203 [Google Scholar]
  87. Colgan SP, Parkos CA, Matthews JB, D'Andrea L, Awtrey CS. 87.  et al. 1994. Interferon-γ induces a surface phenotype switch in intestinal epithelia: downregulation of ion transport and upregulation of immune accessory ligands. Am. J. Physiol. Cell Physiol. 267:C402–C10 [Google Scholar]
  88. Munn DH, Mellor AL. 88.  2013. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol. 34:137–43 [Google Scholar]
  89. Harrington L, Srikanth CV, Antony R, Rhee SJ, Mellor AL. 89.  et al. 2008. Deficiency of indoleamine 2,3-dioxygenase enhances commensal-induced antibody responses and protects against Citrobacter rodentium-induced colitis. Infect. Immun. 76:3045–53 [Google Scholar]
  90. Hansen JJ, Holt L, Sartor RB. 90.  2009. Gene expression patterns in experimental colitis in IL-10-deficient mice. Inflamm. Bowel Dis. 15:890–99 [Google Scholar]
  91. Wolf AM, Wolf D, Rumpold H, Moschen AR, Kaser A. 91.  et al. 2004. Overexpression of indoleamine 2,3-dioxygenase in human inflammatory bowel disease. Clin. Immunol. 113:47–55 [Google Scholar]
  92. Gurtner GJ, Newberry RD, Schloemann SR, McDonald KG, Stenson WF. 92.  2003. Inhibition of indoleamine 2,3-dioxygenase augments trinitrobenzene sulfonic acid colitis in mice. Gastroenterology 125:1762–73 [Google Scholar]
  93. Jasperson LK, Bucher C, Panoskaltsis-Mortari A, Mellor AL, Munn DH, Blazar BR. 93.  2009. Inducing the tryptophan catabolic pathway, indoleamine 2,3-dioxygenase (IDO), for suppression of graft-versus-host disease (GVHD) lethality. Blood 114:5062–70 [Google Scholar]
  94. Kawamoto S, Maruya M, Kato LM, Suda W, Atarashi K. 94.  et al. 2014. Foxp3+ T cells regulate immunoglobulin A selection and facilitate diversification of bacterial species responsible for immune homeostasis. Immunity 41:152–65 [Google Scholar]
  95. Moon C, Baldridge MT, Wallace MA, Burnham CA, Virgin HW, Stappenbeck TS. 95.  2015. Vertically transmitted faecal IgA levels determine extra-chromosomal phenotypic variation. Nature 521:90–93 [Google Scholar]
  96. Palm NW, de Zoete MR, Cullen TW, Barry NA, Stefanowski J. 96.  et al. 2014. Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease. Cell 158:1000–10 [Google Scholar]
  97. Karhausen J, Haase VH, Colgan SP. 97.  2005. Inflammatory hypoxia: role of hypoxia-inducible factor. Cell Cycle 4:256–58 [Google Scholar]
  98. Nakahama T, Kimura A, Nguyen NT, Chinen I, Hanieh H. 98.  et al. 2011. Aryl hydrocarbon receptor deficiency in T cells suppresses the development of collagen-induced arthritis. PNAS 108:14222–27 [Google Scholar]
  99. Stockinger B, Di Meglio P, Gialitakis M, Duarte JH. 99.  2014. The aryl hydrocarbon receptor: multitasking in the immune system. Annu. Rev. Immunol. 32:403–32 [Google Scholar]
  100. Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF. 100.  et al. 2008. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 453:65–71 [Google Scholar]
  101. Di Meglio P, Duarte JH, Ahlfors H, Owens ND, Li Y. 101.  et al. 2014. Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions. Immunity 40:989–1001 [Google Scholar]
  102. Jeong KT, Hwang SJ, Oh GS, Park JH. 102.  2012. FICZ, a tryptophan photoproduct, suppresses pulmonary eosinophilia and Th2-type cytokine production in a mouse model of ovalbumin-induced allergic asthma. Int. Immunopharmacol. 13:377–85 [Google Scholar]
  103. Monteleone I, Rizzo A, Sarra M, Sica G, Sileri P. 103.  et al. 2011. Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology 141:237–48.e1 [Google Scholar]
  104. Zelante T, Iannitti RG, Cunha C, De Luca A, Giovannini G. 104.  et al. 2013. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39:372–85 [Google Scholar]
  105. Glover LE, Bowers BE, Saeedi B, Ehrentraut SF, Campbell EL. 105.  et al. 2013. Control of creatine metabolism by HIF is an endogenous mechanism of barrier regulation in colitis. PNAS 110:19820–25 [Google Scholar]
  106. Wyss M, Kaddurah-Daouk R. 106.  2000. Creatine and creatinine metabolism. Physiol. Rev. 80:1107–213 [Google Scholar]
  107. Ivanov AI, Parkos CA, Nusrat A. 107.  2010. Cytoskeletal regulation of epithelial barrier function during inflammation. Am. J. Pathol. 177:512–24 [Google Scholar]
  108. Turner JR. 108.  2009. Intestinal mucosal barrier function in health and disease. Nat. Rev. Immunol. 9:799–809 [Google Scholar]
  109. Song JC, Hrnjez BJ, Farokhzad OC, Matthews JB. 109.  1999. PKC-epsilon regulates basolateral endocytosis in human T84 intestinal epithelia: role of F-actin and MARCKS. Am. J. Physiol. Cell Physiol. 277:C1239–49 [Google Scholar]
  110. Daniel JL, Molish IR, Robkin L, Holmsen H. 110.  1986. Nucleotide exchange between cytosolic ATP and F-actin-bound ADP may be a major energy-utilizing process in unstimulated platelets. Eur. J. Biochem. 156:677–84 [Google Scholar]
  111. Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. 111.  2012. Diversity, stability and resilience of the human gut microbiota. Nature 489:220–30 [Google Scholar]
  112. Hamer HM, Jonkers D, Venema K, Vanhoutvin S, Troost FJ, Brummer RJ. 112.  2008. Review article: the role of butyrate on colonic function. Aliment. Pharmacol. Ther. 27:104–19 [Google Scholar]
  113. Blouin JM, Penot G, Collinet M, Nacfer M, Forest C. 113.  et al. 2011. Butyrate elicits a metabolic switch in human colon cancer cells by targeting the pyruvate dehydrogenase complex. Int. J. Cancer 128:2591–601 [Google Scholar]
  114. Kelly CJ, Zheng L, Campbell EL, Saeedi B, Scholz CC. 114.  et al. 2015. Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function. Cell Host Microbe 17:662–71 [Google Scholar]
  115. Colgan SP, Taylor CT. 115.  2010. Hypoxia: an alarm signal during intestinal inflammation. Nat. Rev. Gastroenterol. Hepatol. 7:281–87 [Google Scholar]
  116. Ploger S, Stumpff F, Penner GB, Schulzke JD, Gabel G. 116.  et al. 2012. Microbial butyrate and its role for barrier function in the gastrointestinal tract. Ann. N. Y. Acad. Sci. 1258:52–59 [Google Scholar]
  117. Ito H, Tanabe H, Kawagishi H, Tadashi W, Yasuhiko T. 117.  et al. 2009. Short-chain inulin-like fructans reduce endotoxin and bacterial translocations and attenuate development of TNBS-induced colitis in rats. Dig. Dis. Sci. 54:2100–8 [Google Scholar]
  118. Morita T, Tanabe H, Sugiyama K, Kasaoka S, Kiriyama S. 118.  2004. Dietary resistant starch alters the characteristics of colonic mucosa and exerts a protective effect on trinitrobenzene sulfonic acid-induced colitis in rats. Biosci. Biotechnol. Biochem. 68:2155–64 [Google Scholar]
  119. Videla S, Vilaseca J, Antolin M, Garcia-Lafuente A, Guarner F. 119.  et al. 2001. Dietary inulin improves distal colitis induced by dextran sodium sulfate in the rat. Am. J. Gastroenterol. 96:1486–93 [Google Scholar]
  120. Cresci G, Nagy LE, Ganapathy V. 120.  2013. Lactobacillus GG and tributyrin supplementation reduce antibiotic-induced intestinal injury. JPEN J. Parenter. Enteral Nutr. 37:763–74 [Google Scholar]
  121. Leonel AJ, Teixeira LG, Oliveira RP, Santiago AF, Batista NV. 121.  et al. 2013. Antioxidative and immunomodulatory effects of tributyrin supplementation on experimental colitis. Br. J. Nutr. 109:1396–407 [Google Scholar]
  122. Machiels K, Joossens M, Sabino J, De Preter V, Arijs I. 122.  et al. 2014. A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut 63:1275–83 [Google Scholar]
  123. Eeckhaut V, Machiels K, Perrier C, Romero C, Maes S. 123.  et al. 2013. Butyricicoccus pullicaecorum in inflammatory bowel disease. Gut 62:1745–52 [Google Scholar]
  124. Sokol H, Seksik P, Furet JP, Firmesse O, Nion-Larmurier I. 124.  et al. 2009. Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflamm. Bowel Dis. 15:1183–89 [Google Scholar]
  125. Roediger WE, Nance S. 125.  1986. Metabolic induction of experimental ulcerative colitis by inhibition of fatty acid oxidation. Br. J. Exp. Pathol. 67:773–82 [Google Scholar]
  126. Bar F, Bochmann W, Widok A, von Medem K, Pagel R. 126.  et al. 2013. Mitochondrial gene polymorphisms that protect mice from colitis. Gastroenterology 145:1055–63.e3 [Google Scholar]
  127. Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP. 127.  et al. 2012. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491:119–24 [Google Scholar]
  128. Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y. 128.  et al. 2013. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500:232–36 [Google Scholar]
  129. Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA. 129.  et al. 2013. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341:569–73 [Google Scholar]
  130. Kim MH, Kang SG, Park JH, Yanagisawa M, Kim CH. 130.  2013. Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology 145:396–406 [Google Scholar]
  131. Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F. 131.  et al. 2009. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461:1282–86 [Google Scholar]
  132. Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R. 132.  et al. 2014. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40:128–39 [Google Scholar]
  133. Kaelin WG Jr, Ratcliffe PJ. 133.  2008. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol. Cell 30:393–402 [Google Scholar]
  134. Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J. 134.  et al. 2001. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107:43–54 [Google Scholar]
  135. Cummins EP, Berra E, Comerford KM, Ginouves A, Fitzgerald KT. 135.  et al. 2006. Prolyl hydroxylase-1 negatively regulates IκB kinase-β, giving insight into hypoxia-induced NFκB activity. PNAS 103:18154–59 [Google Scholar]
  136. Aragones J, Schneider M, Van Geyte K, Fraisl P, Dresselaers T. 136.  et al. 2008. Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nat. Genet. 40:170–80 [Google Scholar]
  137. Schneider M, Van Geyte K, Fraisl P, Kiss J, Aragones J. 137.  et al. 2009. Loss or silencing of the PHD1 prolyl hydroxylase protects livers of mice against ischemia/reperfusion injury. Gastroenterology 38:1143–54.e1–2 [Google Scholar]
  138. Tambuwala MM, Cummins EP, Lenihan CR, Kiss J, Stauch M. 138.  et al. 2010. Loss of prolyl hydroxylase-1 protects against colitis through reduced epithelial cell apoptosis and increased barrier function. Gastroenterology 139:2093–101 [Google Scholar]
  139. Mazzone M, Dettori D, Leite de Oliveira R, Loges S. 139.  et al. 2009. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 136:839–51 [Google Scholar]
  140. Ozolins TR, Fisher TS, Nadeau DM, Stock JL, Klein AS. 140.  et al. 2009. Defects in embryonic development of EGLN1/PHD2 knockdown transgenic mice are associated with induction of Igfbp in the placenta. Biochem. Biophys. Res. Commun. 390:372–76 [Google Scholar]
  141. Bishop T, Gallagher D, Pascual A, Lygate CA, de Bono JP. 141.  et al. 2008. Abnormal sympathoadrenal development and systemic hypotension in PHD3−/− mice. Mol. Cell. Biol. 28:3386–400 [Google Scholar]
  142. Mole DR, Schlemminger I, McNeill LA, Hewitson KS, Pugh CW. 142.  et al. 2003. 2-oxoglutarate analogue inhibitors of HIF prolyl hydroxylase. Bioorg. Med. Chem. Lett. 13:2677–80 [Google Scholar]
  143. Masson N, Ratcliffe PJ. 143.  2003. HIF prolyl and asparaginyl hydroxylases in the biological response to intracellular O(2) levels. J. Cell Sci. 116:3041–49 [Google Scholar]
  144. Schofield CJ, Ratcliffe PJ. 144.  2004. Oxygen sensing by HIF hydroxylases. Nat. Rev. Mol. Cell Biol. 5:343–54 [Google Scholar]
  145. Bruick RK. 145.  2003. Oxygen sensing in the hypoxic response pathway: regulation of the hypoxia-inducible transcription factor. Genes Dev. 17:2614–23 [Google Scholar]
  146. Schlemminger I, Mole DR, McNeill LA, Dhanda A, Hewitson KS. 146.  et al. 2003. Analogues of dealanylalahopcin are inhibitors of human HIF prolyl hydroxylases. Bioorg. Med. Chem. Lett. 13:1451–54 [Google Scholar]
  147. Nwogu JI, Geenen D, Bean M, Brenner MC, Huang X, Buttrick PM. 147.  2001. Inhibition of collagen synthesis with prolyl 4-hydroxylase inhibitor improves left ventricular function and alters the pattern of left ventricular dilatation after myocardial infarction. Circulation 104:2216–21 [Google Scholar]
  148. Rankin EB, Biju MP, Liu Q, Unger TL, Rha J. 148.  et al. 2007. Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J. Clin. Investig. 117:1068–77 [Google Scholar]
  149. Percy MJ, Furlow PW, Lucas GS, Li X, Lappin TR. 149.  et al. 2008. A gain-of-function mutation in the HIF2A gene in familial erythrocytosis. N. Engl. J. Med. 358:162–68 [Google Scholar]
  150. Keely S, Campbell EL, Baird AW, Hansbro PM, Shalwitz RA. 150.  et al. 2014. Contribution of epithelial innate immunity to systemic protection afforded by prolyl hydroxylase inhibition in murine colitis. Mucosal Immunol. 7:114–23 [Google Scholar]
  151. Okumura CY, Hollands A, Tran DN, Olson J, Dahesh S. 151.  et al. 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. 28:1079–89 [Google Scholar]
  152. Mikus P, Zundel W. 152.  2005. COPing with hypoxia. Semin. Cell Dev. Biol. 16:462–73 [Google Scholar]
  153. Boh BK, Smith PG, Hagen T. 153.  2011. Neddylation-induced conformational control regulates cullin RING ligase activity in vivo. J. Mol. Biol. 409:136–45 [Google Scholar]
  154. Soucy TA, Smith PG, Milhollen MA, Berger AJ, Gavin JM. 154.  et al. 2009. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature 458:732–36 [Google Scholar]
  155. Khoury J, Ibla JC, Neish AS, Colgan SP. 155.  2007. Antiinflammatory adaptation to hypoxia through adenosine-mediated cullin-1 deneddylation. J. Clin. Investig. 117:703–11 [Google Scholar]
  156. Curtis VF, Ehrentraut SF, Campbell EL, Glover LE, Bayless AJ. 156.  et al. 2015. Stabilization of HIF through inhibition of Cullin-2 neddylation is protective in mucosal inflammatory responses. FASEB J. 29:208–15 [Google Scholar]
  157. Ehrentraut SF, Kominsky DJ, Glover LE, Campbell EL, Kelly CJ. 157.  et al. 2013. Central role for endothelial human deneddylase-1/SENP8 in fine-tuning the vascular inflammatory response. J. Immunol. 190:392–400 [Google Scholar]
  158. Kong D, Park EJ, Stephen AG, Calvani M, Cardellina JH. 158.  et al. 2005. Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res. 65:9047–55 [Google Scholar]
  159. Wang R, Zhou S, Li S. 159.  2011. Cancer therapeutic agents targeting hypoxia-inducible factor-1. Curr. Med. Chem. 18:3168–89 [Google Scholar]
  160. Zhang H, Qian DZ, Tan YS, Lee K, Gao P. 160.  et al. 2008. Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth. PNAS 105:19579–86 [Google Scholar]
  161. Xia Y, Choi HK, Lee K. 161.  2012. Recent advances in hypoxia-inducible factor (HIF)-1 inhibitors. Eur. J. Med. Chem. 49:24–40 [Google Scholar]
  162. Jaen O, Rulle S, Bessis N, Zago A, Boissier MC, Falgarone G. 162.  2009. Dendritic cells modulated by innate immunity improve collagen-induced arthritis and induce regulatory T cells in vivo. Immunology 126:35–44 [Google Scholar]
  163. Szanto S, Koreny T, Mikecz K, Glant TT, Szekanecz Z, Varga J. 163.  2007. Inhibition of indoleamine 2,3-dioxygenase-mediated tryptophan catabolism accelerates collagen-induced arthritis in mice. Arthritis Res. Ther. 9:R50 [Google Scholar]
  164. Hayashi T, Beck L, Rossetto C, Gong X, Takikawa O. 164.  et al. 2004. Inhibition of experimental asthma by indoleamine 2,3-dioxygenase. J. Clin. Investig. 114:270–79 [Google Scholar]
  165. Kwidzinski E, Bunse J, Aktas O, Richter D, Mutlu L. 165.  et al. 2005. Indolamine 2,3-dioxygenase is expressed in the CNS and down-regulates autoimmune inflammation. FASEB J. 19:1347–49 [Google Scholar]
  166. Jasperson LK, Bucher C, Panoskaltsis-Mortari A, Taylor PA, Mellor AL. 166.  et al. 2008. Indoleamine 2,3-dioxygenase is a critical regulator of acute graft-versus-host disease lethality. Blood 111:3257–65 [Google Scholar]
  167. Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L. 167.  et al. 2008. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453:106–9 [Google Scholar]
  168. Quintana FJ, Murugaiyan G, Farez MF, Mitsdoerffer M, Tukpah AM. 168.  et al. 2010. An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis. PNAS 107:20768–73 [Google Scholar]
  169. Luebke RW, Copeland CB, Daniels M, Lambert AL, Gilmour MI. 169.  2001. Suppression of allergic immune responses to house dust mite (HDM) in rats exposed to 2,3,7,8-TCDD. Toxicol. Sci. 62:71–79 [Google Scholar]
  170. Moon DO, Kim MO, Lee HJ, Choi YH, Park YM. 170.  et al. 2008. Curcumin attenuates ovalbumin-induced airway inflammation by regulating nitric oxide. Biochem. Biophys. Res. Commun. 375:275–79 [Google Scholar]
  171. Rico de Souza A, Zago M, Pollock SJ, Sime PJ, Phipps RP, Baglole CJ. 171.  2011. Genetic ablation of the aryl hydrocarbon receptor causes cigarette smoke-induced mitochondrial dysfunction and apoptosis. J. Biol. Chem. 286:43214–28 [Google Scholar]
  172. Xue J, Nguyen DT, Habtezion A. 172.  2012. Aryl hydrocarbon receptor regulates pancreatic IL-22 production and protects mice from acute pancreatitis. Gastroenterology 143:1670–80 [Google Scholar]
  173. Ji T, Xu C, Sun L, Yu M, Peng K. 173.  et al. 2015. Aryl hydrocarbon receptor activation down-regulates IL-7 and reduces inflammation in a mouse model of DSS-induced colitis. Dig. Dis. Sci. 60:1958–66 [Google Scholar]
  174. Chinen I, Nakahama T, Kimura A, Nguyen NT, Takemori H. 174.  et al. 2015. The aryl hydrocarbon receptor/microRNA-212/132 axis in T cells regulates IL-10 production to maintain intestinal homeostasis. Int. Immunol. 27:405–15 [Google Scholar]

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