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Journal of Molecular Medicine

, Volume 96, Issue 12, pp 1293–1306 | Cite as

Hypoxia-inducible factor-1α regulation of myeloid cells

  • C. L. StothersEmail author
  • L. Luan
  • B. A. Fensterheim
  • J. K. Bohannon
Review

Abstract

Hematopoietic myeloblasts give rise to macrophages, dendritic cells, and neutrophils. Circulating myeloid cells detect invading microbes using pattern recognition receptors and subsequently orchestrate an innate immune response to contain and kill the pathogens. This innate immune response establishes an inflammatory niche characterized by hypoxia due to host and pathogen factors. Hypoxia-inducible factor (HIF) transcription factors are the primary regulators of the myeloid response to hypoxia. In particular, HIF-1α is a critical hub that integrates hypoxic and immunogenic signals during infection or inflammation. Hypoxia induces HIF-1α stabilization, which drives metabolic and phenotypic reprogramming of myeloid cells to maximize antimicrobial potential. HIF-1α activity in myeloid-derived cells enhances the host response to infection, but may also play a role in pathogenic inflammatory processes, such as atherosclerosis. In this review, we summarize recent advances that have elucidated the mechanism by which myeloid cells regulate HIF-1α activity and, in turn, how HIF-1α shapes myeloid cell function.

Keywords

Myeloid HIF Immunometabolism Hypoxia Inflammation 

Abbreviations

2-DG

2-deoxyglucose

ABCA1

ATP-binding cassette subfamily a member 1

ATP

Adenosine triphosphate

CCR

C-C chemokine receptor

CD

Cluster of differentiation

CIC

Mitochondrial citrate carrier

CRISPR

Clustered regularly interspaced short palindromic repeats

DCs

Dendritic cells

DMOG

Dimethyloxallyl glycine

DSS

Dextran sodium sulfate

FAO

Fatty acid oxidation

FIH-1

Protein factor inhibiting HIF-1

GLUT1

Glucose transporter 1

Gulo

L-gulono-γ-lactone oxidase

HIF

Hypoxia-inducible factor

HREs

HIF response elements

IBD

Inflammatory bowel disease

IFN-γ

Interferon-gamma

IKK-β

Iκb kinase beta

IL

Interleukin

iNOS

Inducible nitric oxide synthase

IκB

Inhibitor of nuclear factor-kappa B

KLF-2

Krüppel-like factor 2

LDL

Low-density lipoprotein

LPS

Lipopolysaccharide

MHC

Major histocompatibility complex

MIP-1β

Macrophage inflammatory protein-1β

MPLA

Monophosphoryl lipid A

mTOR

Mechanistic target of rapamycin

NETs

Neutrophil extracellular traps

NF-κB

Nuclear factor of kappa B

NO

Nitric oxide

oxLDL

oxidized low-density lipoprotein

PHDs

Prolyl-4-hydoxylase domain enzymes

PI3K

Phosphoinositide 3-kinase

PK

Pyruvate kinase

PKM

Pyruvate kinase muscle isoenzyme

PPP

Pentose phosphate pathway

pVHL

Von Hippel-Lindau E3 ubiquitin ligase

RNS

Reactive nitrogen species

ROS

Reactive oxygen species

SDH

Succinate dehydrogenase

SIRT1/2

Sirtuin deacetylase 1 and 2

TCA cycle

Tricarboxylic acid cycle

Th1/2

T helper cell type 1 and 2

TLR

Toll-like receptor

Treg

Regulatory T cell

VEGF

Vascular endothelial growth factor

Notes

Funding information

This work was supported by the NIH grants R01 GM121711 (to JKB) and T32 GM007347 Medical Scientist Training Program Grant (to CLS and BAF).

Compliance with ethical standards

Conflicts of interest

The authors declare that there are no conflicts of interest.

References

  1. 1.
    Borregaard N, Elsbach P, Ganz T, Garred P, Svejgaard A (2000) Innate immunity: from plants to humans. Immunol Today 21(2):68–70PubMedGoogle Scholar
  2. 2.
    De Kleer I, Willems F, Lambrecht B, Goriely S (2014) Ontogeny of myeloid cells. Front Immunol 5:423.  https://doi.org/10.3389/fimmu.2014.00423 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K (2010) Development of monocytes, macrophages, and dendritic cells. Science 327(5966):656–661PubMedPubMedCentralGoogle Scholar
  4. 4.
    O'Neill LA, Golenbock D, Bowie AG (2013) The history of Toll-like receptors—redefining innate immunity. Nat Rev Immunol 13(6):453–460PubMedGoogle Scholar
  5. 5.
    Saadi S, Wrenshall LE, Platt JL (2002) Regional manifestations and control of the immune system. FASEB J 16(8):849–856PubMedGoogle Scholar
  6. 6.
    Nizet V, Johnson RS (2009) Interdependence of hypoxic and innate immune responses. Nat Rev Immunol 9(9):609–617PubMedPubMedCentralGoogle Scholar
  7. 7.
    Cummins EP, Taylor CT (2005) Hypoxia-responsive transcription factors. Pflugers Archiv: European Journal of Physiology 450(6):363–371PubMedGoogle Scholar
  8. 8.
    Taylor CT, Colgan SP (2017) Regulation of immunity and inflammation by hypoxia in immunological niches. Nat Rev Immunol 17(12):774–785PubMedGoogle Scholar
  9. 9.
    Kaelin WG Jr, Ratcliffe PJ (2008) Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 30(4):393–402PubMedGoogle Scholar
  10. 10.
    Corcoran SE, O'Neill LA (2016) HIF1alpha and metabolic reprogramming in inflammation. J Clin Invest 126(10):3699–3707PubMedPubMedCentralGoogle Scholar
  11. 11.
    Imtiyaz HZ, Williams EP, Hickey MM, Patel SA, Durham AC, Yuan LJ, Hammond R, Gimotty PA, Keith B, Simon MC (2010) Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation. J Clin Invest 120(8):2699–2714PubMedPubMedCentralGoogle Scholar
  12. 12.
    Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A 92(12):5510–5514PubMedPubMedCentralGoogle Scholar
  13. 13.
    Wang GL, Semenza GL (1995) Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 270(3):1230–1237PubMedGoogle Scholar
  14. 14.
    Semenza GL, Roth PH, Fang HM, Wang GL (1994) Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem 269(38):23757–23763PubMedGoogle Scholar
  15. 15.
    Koyasu S, Kobayashi M, Goto Y, Hiraoka M, Harada H (2018) Regulatory mechanisms of hypoxia-inducible factor 1 activity: two decades of knowledge. Cancer Sci 109(3):560–571PubMedPubMedCentralGoogle Scholar
  16. 16.
    Kuhlicke J, Frick JS, Morote-Garcia JC, Rosenberger P, Eltzschig HK (2007) Hypoxia inducible factor (HIF)-1 coordinates induction of Toll-like receptors TLR2 and TLR6 during hypoxia. PLoS One 2(12):e1364.  https://doi.org/10.1371/journal.pone.0001364 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Zinkernagel AS, Peyssonnaux C, Johnson RS, Nizet V (2008) Pharmacologic augmentation of hypoxia-inducible factor-1alpha with mimosine boosts the bactericidal capacity of phagocytes. J Infect Dis 197(2):214–217PubMedGoogle Scholar
  18. 18.
    Casazza A, Laoui D, Wenes M, Rizzolio S, Bassani N, Mambretti M, Deschoemaeker S, Van Ginderachter JA, Tamagnone L, Mazzone M (2013) Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell 24(6):695–709PubMedGoogle Scholar
  19. 19.
    Thompson AA, Elks PM, Marriott HM, Eamsamarng S, Higgins KR, Lewis A, Williams L, Parmar S, Shaw G, McGrath EE, Formenti F, Van Eeden FJ, Kinnula VL, Pugh CW, Sabroe I, Dockrell DH, Chilvers ER, Robbins PA, Percy MJ, Simon MC, Johnson RS, Renshaw SA, Whyte MK, Walmsley SR (2014) Hypoxia-inducible factor 2alpha regulates key neutrophil functions in humans, mice, and zebrafish. Blood 123(3):366–376PubMedPubMedCentralGoogle Scholar
  20. 20.
    Devraj G, Beerlage C, Brune B, Kempf VA (2017) Hypoxia and HIF-1 activation in bacterial infections. Microbes Infect 19(3):144–156PubMedGoogle Scholar
  21. 21.
    Colgan SP, Campbell EL, Kominsky DJ (2016) Hypoxia and mucosal inflammation. Annu Rev Pathol 11:77–100PubMedPubMedCentralGoogle Scholar
  22. 22.
    Salceda S, Caro J (1997) Hypoxia-inducible factor 1α (HIF-1α) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. J Biol Chem 272(36):22642–22647PubMedGoogle Scholar
  23. 23.
    Frede S, Stockmann C, Freitag P, Fandrey J (2006) Bacterial lipopolysaccharide induces HIF-1 activation in human monocytes via p44/42 MAPK and NF-kappaB. Biochem J 396(3):517–527PubMedPubMedCentralGoogle Scholar
  24. 24.
    Schuster DP, Brody SL, Zhou Z, Bernstein M, Arch R, Link D, Mueckler M (2007) Regulation of lipopolysaccharide-induced increases in neutrophil glucose uptake. Am J Physiol Lung Cell Mol Physiol 292(4):L845–L851PubMedGoogle Scholar
  25. 25.
    Blouin CC, Page EL, Soucy GM, Richard DE (2004) Hypoxic gene activation by lipopolysaccharide in macrophages: implication of hypoxia-inducible factor 1alpha. Blood 103(3):1124–1130PubMedGoogle Scholar
  26. 26.
    Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, Frezza C, Bernard NJ, Kelly B, Foley NH, Zheng L, Gardet A, Tong Z, Jany SS, Corr SC, Haneklaus M, Caffrey BE, Pierce K, Walmsley S, Beasley FC, Cummins E, Nizet V, Whyte M, Taylor CT, Lin H, Masters SL, Gottlieb E, Kelly VP, Clish C, Auron PE, Xavier RJ, O'Neill LA (2013) Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature 496(7444):238–242PubMedPubMedCentralGoogle Scholar
  27. 27.
    Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, Johnson RS, Haddad GG, Karin M (2008) NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature 453(7196):807–811PubMedPubMedCentralGoogle Scholar
  28. 28.
    Cummins EP, Berra E, Comerford KM, Ginouves A, Fitzgerald KT, Seeballuck F, Godson C, Nielsen JE, Moynagh P, Pouyssegur J, Taylor CT (2006) Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proc Natl Acad Sci U S A 103(48):18154–18159PubMedPubMedCentralGoogle Scholar
  29. 29.
    Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML (2002) Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science 295(5556):858–861Google Scholar
  30. 30.
    Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK (2002) FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev 16(12):1466–1471PubMedPubMedCentralGoogle Scholar
  31. 31.
    Sakamoto T, Seiki M (2009) Mint3 enhances the activity of hypoxia-inducible factor-1 (HIF-1) in macrophages by suppressing the activity of factor inhibiting HIF-1. J Biol Chem 284(44):30350–30359PubMedPubMedCentralGoogle Scholar
  32. 32.
    Hara T, Mimura K, Abe T, Shioi G, Seiki M, Sakamoto T (2011) Deletion of the Mint3/Apba3 gene in mice abrogates macrophage functions and increases resistance to lipopolysaccharide-induced septic shock. J Biol Chem 286(37):32542–32551PubMedPubMedCentralGoogle Scholar
  33. 33.
    Cockman ME, Lancaster DE, Stolze IP, Hewitson KS, McDonough MA, Coleman ML, Coles CH, Yu X, Hay RT, Ley SC, Pugh CW, Oldham NJ, Masson N, Schofield CJ, Ratcliffe PJ (2006) Posttranslational hydroxylation of ankyrin repeats in IkappaB proteins by the hypoxia-inducible factor (HIF) asparaginyl hydroxylase, factor inhibiting HIF (FIH). Proc Natl Acad Sci U S A 103(40):14767–14772PubMedPubMedCentralGoogle Scholar
  34. 34.
    Shin DH, Li SH, Yang SW, Lee BL, Lee MK, Park JW (2009) Inhibitor of nuclear factor-kappaB alpha derepresses hypoxia-inducible factor-1 during moderate hypoxia by sequestering factor inhibiting hypoxia-inducible factor from hypoxia-inducible factor 1alpha. FEBS J 276(13):3470–3480PubMedGoogle Scholar
  35. 35.
    Liu TF, Vachharajani VT, Yoza BK, McCall CE (2012) NAD+-dependent sirtuin 1 and 6 proteins coordinate a switch from glucose to fatty acid oxidation during the acute inflammatory response. J Biol Chem 287(31):25758–25769PubMedPubMedCentralGoogle Scholar
  36. 36.
    Yoshizaki T, Milne JC, Imamura T, Schenk S, Sonoda N, Babendure JL, Lu JC, Smith JJ, Jirousek MR, Olefsky JM (2009) SIRT1 exerts anti-inflammatory effects and improves insulin sensitivity in adipocytes. Mol Cell Biol 29(5):1363–1374PubMedGoogle Scholar
  37. 37.
    Kauppinen A, Suuronen T, Ojala J, Kaarniranta K, Salminen A (2013) Antagonistic crosstalk between NF-kappaB and SIRT1 in the regulation of inflammation and metabolic disorders. Cell Signal 25(10):1939–1948CrossRefGoogle Scholar
  38. 38.
    Seo KS, Park JH, Heo JY, Jing K, Han J, Min KN, Kim C, Koh GY, Lim K, Kang GY, Uee Lee J, Yim YH, Shong M, Kwak TH, Kweon GR (2015) SIRT2 regulates tumour hypoxia response by promoting HIF-1alpha hydroxylation. Oncogene 34(11):1354–1362PubMedGoogle Scholar
  39. 39.
    Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292(5516):468–472PubMedGoogle Scholar
  40. 40.
    Hams E, Saunders SP, Cummins EP, O’Connor A, Tambuwala MT, Gallagher WM, Byrne A, Campos-Torres A, Moynagh PM, Jobin C, Taylor CT, Fallon PG (2011) The hydroxylase inhibitor DMOG attenuates endotoxic shock via alternative activation of macrophages and IL-10 production by B-1 cells. Shock (Augusta, GA) 36(3):295–302Google Scholar
  41. 41.
    Epelman S, Lavine KJ, Randolph GJ (2014) Origin and functions of tissue macrophages. Immunity 41(1):21–35PubMedPubMedCentralGoogle Scholar
  42. 42.
    Wynn TA, Chawla A, Pollard JW (2013) Macrophage biology in development, homeostasis and disease. Nature 496(7446):445–455PubMedPubMedCentralGoogle Scholar
  43. 43.
    Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8(12):958–969PubMedPubMedCentralGoogle Scholar
  44. 44.
    Mills EL, Kelly B, Logan A, Costa AS, Varma M, Bryant CE, Tourlomousis P, Dabritz JH, Gottlieb E, Latorre I, Corr SC, McManus G, Ryan D, Jacobs HT, Szibor M, Xavier RJ, Braun T, Frezza C, Murphy MP, O'Neill LA (2016) Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 167(2):457–470.e413PubMedPubMedCentralGoogle Scholar
  45. 45.
    Fitzpatrick SF, Tambuwala MM, Bruning U, Schaible B, Scholz CC, Byrne A, O'Connor A, Gallagher WM, Lenihan CR, Garvey JF, Howell K, Fallon PG, Cummins EP, Taylor CT (2011) An intact canonical NF-kappaB pathway is required for inflammatory gene expression in response to hypoxia. J Immunol 186(2):1091–1096PubMedGoogle Scholar
  46. 46.
    Werno C, Menrad H, Weigert A, Dehne N, Goerdt S, Schledzewski K, Kzhyshkowska J, Brune B (2010) Knockout of HIF-1alpha in tumor-associated macrophages enhances M2 polarization and attenuates their pro-angiogenic responses. Carcinogenesis 31(10):1863–1872PubMedGoogle Scholar
  47. 47.
    Hard GC (1970) Some biochemical aspects of the immune macrophage. Br J Exp Pathol 51(1):97–105PubMedPubMedCentralGoogle Scholar
  48. 48.
    Freemerman AJ, Johnson AR, Sacks GN, Milner JJ, Kirk EL, Troester MA, Macintyre AN, Goraksha-Hicks P, Rathmell JC, Makowski L (2014) Metabolic reprogramming of macrophages: glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype. J Biol Chem 289(11):7884–7896PubMedPubMedCentralGoogle Scholar
  49. 49.
    Haschemi A, Kosma P, Gille L, Evans CR, Burant CF, Starkl P, Knapp B, Haas R, Schmid JA, Jandl C, Amir S, Lubec G, Park J, Esterbauer H, Bilban M, Brizuela L, Pospisilik JA, Otterbein LE, Wagner O (2012) The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. Cell Metab 15(6):813–826PubMedPubMedCentralGoogle Scholar
  50. 50.
    Palsson-McDermott EM, Curtis AM, Goel G, Lauterbach MA, Sheedy FJ, Gleeson LE, van den Bosch MW, Quinn SR, Domingo-Fernandez R, Johnston DG, Jiang JK, Israelsen WJ, Keane J, Thomas C, Clish C, Vander Heiden M, Xavier RJ, O'Neill LA (2015) Pyruvate kinase M2 regulates Hif-1alpha activity and IL-1beta induction and is a critical determinant of the Warburg effect in LPS-activated macrophages. Cell Metab 21(1):65–80PubMedPubMedCentralGoogle Scholar
  51. 51.
    Infantino V, Iacobazzi V, Menga A, Avantaggiati ML, Palmieri F (2014) A key role of the mitochondrial citrate carrier (SLC25A1) in TNFalpha- and IFNgamma-triggered inflammation. Biochim Biophys Acta 1839(11):1217–1225PubMedPubMedCentralGoogle Scholar
  52. 52.
    Calvani M, Comito G, Giannoni E, Chiarugi P (2012) Time-dependent stabilization of hypoxia inducible factor-1alpha by different intracellular sources of reactive oxygen species. PLoS One 7(10):e38388.  https://doi.org/10.1371/journal.pone.0038388 CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Masson N, Singleton RS, Sekirnik R, Trudgian DC, Ambrose LJ, Miranda MX, Tian YM, Kessler BM, Schofield CJ, Ratcliffe PJ (2012) The FIH hydroxylase is a cellular peroxide sensor that modulates HIF transcriptional activity. EMBO Rep 13(3):251–257PubMedPubMedCentralGoogle Scholar
  54. 54.
    Jha AK, Huang SC, Sergushichev A, Lampropoulou V, Ivanova Y, Loginicheva E, Chmielewski K, Stewart KM, Ashall J, Everts B, Pearce EJ, Driggers EM, Artyomov MN (2015) Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42(3):419–430PubMedGoogle Scholar
  55. 55.
    Cramer T, Yamanishi Y, Clausen BE, Forster I, Pawlinski R, Mackman N, Haase VH, Jaenisch R, Corr M, Nizet V, Firestein GS, Gerber HP, Ferrara N, Johnson RS (2003) HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 112(5):645–657PubMedPubMedCentralGoogle Scholar
  56. 56.
    Kim SY, Choi YJ, Joung SM, Lee BH, Jung YS, Lee JY (2010) Hypoxic stress up-regulates the expression of Toll-like receptor 4 in macrophages via hypoxia-inducible factor. Immunology 129(4):516–524PubMedPubMedCentralGoogle Scholar
  57. 57.
    Kong T, Eltzschig HK, Karhausen J, Colgan SP, Shelley CS (2004) Leukocyte adhesion during hypoxia is mediated by HIF-1-dependent induction of beta2 integrin gene expression. Proc Natl Acad Sci U S A 101(28):10440–10445PubMedPubMedCentralGoogle Scholar
  58. 58.
    Fensterheim BA, Guo Y, Sherwood ER, Bohannon JK (2017) The cytokine response to lipopolysaccharide does not predict the host response to infection. J Immunol 198(8):3264–3273PubMedPubMedCentralGoogle Scholar
  59. 59.
    Anand RJ, Gribar SC, Li J, Kohler JW, Branca MF, Dubowski T, Sodhi CP, Hackam DJ (2007) Hypoxia causes an increase in phagocytosis by macrophages in a HIF-1alpha-dependent manner. J Leukoc Biol 82(5):1257–1265PubMedGoogle Scholar
  60. 60.
    Braverman J, Stanley SA (2017) Nitric oxide modulates macrophage responses to Mycobacterium tuberculosis infection through activation of HIF-1alpha and repression of NF-kappaB. J Immunol 199(5):1805–1816PubMedPubMedCentralGoogle Scholar
  61. 61.
    Bhandari T, Olson J, Johnson RS, Nizet V (2013) HIF-1alpha influences myeloid cell antigen presentation and response to subcutaneous OVA vaccination. J Mol Med (Berlin, Germany) 91(10):1199–1205Google Scholar
  62. 62.
    Cheng SC, Quintin J, Cramer RA, Shepardson KM, Saeed S, Kumar V, Giamarellos-Bourboulis EJ, Martens JH, Rao NA, Aghajanirefah A, Manjeri GR, Li Y, Ifrim DC, Arts RJ, van der Veer BM, Deen PM, Logie C, O'Neill LA, Willems P, van de Veerdonk FL, van der Meer JW, Ng A, Joosten LA, Wijmenga C, Stunnenberg HG, Xavier RJ, Netea MG (2014) mTOR- and HIF-1alpha-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345(6204):1250684PubMedPubMedCentralGoogle Scholar
  63. 63.
    Arts RJ, Novakovic B, Ter Horst R, Carvalho A, Bekkering S, Lachmandas E, Rodrigues F, Silvestre R, Cheng SC, Wang SY, Habibi E, Goncalves LG, Mesquita I, Cunha C, van Laarhoven A, van de Veerdonk FL, Williams DL, van der Meer JW, Logie C, O'Neill LA, Dinarello CA, Riksen NP, van Crevel R, Clish C, Notebaart RA, Joosten LA, Stunnenberg HG, Xavier RJ, Netea MG (2016) Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab 24(6):807–819PubMedPubMedCentralGoogle Scholar
  64. 64.
    Fensterheim BA, Young JD, Luan L, Kleinbard RR, Stothers CL, Patil NK, McAtee-Pereira AG, Guo Y, Trenary I, Hernandez A, Fults JB, Williams DL, Sherwood ER, Bohannon JK (2018) The TLR4 agonist monophosphoryl lipid a drives broad resistance to infection via dynamic reprogramming of macrophage metabolism. J Immunol 200(11):3777–3789PubMedGoogle Scholar
  65. 65.
    Romero CD, Varma TK, Hobbs JB, Reyes A, Driver B, Sherwood ER (2011) The Toll-like receptor 4 agonist monophosphoryl lipid a augments innate host resistance to systemic bacterial infection. Infect Immun 79(9):3576–3587PubMedPubMedCentralGoogle Scholar
  66. 66.
    Netea MG, Joosten LA, Latz E, Mills KH, Natoli G, Stunnenberg HG, O'Neill LA, Xavier RJ (2016) Trained immunity: a program of innate immune memory in health and disease. Science 352(6284):aaf1098PubMedPubMedCentralGoogle Scholar
  67. 67.
    Bekkering S, Arts RJW, Novakovic B, Kourtzelis I, van der Heijden C, Li Y, Popa CD, Ter Horst R, van Tuijl J, Netea-Maier RT, van de Veerdonk FL, Chavakis T, Joosten LAB, van der Meer JWM, Stunnenberg H, Riksen NP, Netea MG (2018) Metabolic induction of trained immunity through the mevalonate pathway. Cell 172(1–2):135–146 e139 PubMedGoogle Scholar
  68. 68.
    Schrum JE, Crabtree JN, Dobbs KR, Kiritsy MC, Reed GW, Gazzinelli RT, Netea MG, Kazura JW, Dent AE, Fitzgerald KA, Golenbock DT (2018) Cutting edge: Plasmodium falciparum induces trained innate immunity. J Immunol 200(4):1243–1248PubMedPubMedCentralGoogle Scholar
  69. 69.
    Quintin J, Saeed S, Martens JHA, Giamarellos-Bourboulis EJ, Ifrim DC, Logie C, Jacobs L, Jansen T, Kullberg BJ, Wijmenga C, Joosten LAB, Xavier RJ, van der Meer JWM, Stunnenberg HG, Netea MG (2012) Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe 12(2):223–232PubMedGoogle Scholar
  70. 70.
    Joosten SA, van Meijgaarden KE, Arend SM, Prins C, Oftung F, Korsvold GE, Kik SV, Arts RJ, van Crevel R, Netea MG, Ottenhoff TH (2018) Mycobacterial growth inhibition is associated with trained innate immunity. J Clin Invest 128(5):1837–1851PubMedPubMedCentralGoogle Scholar
  71. 71.
    Ip WKE, Hoshi N, Shouval DS, Snapper S, Medzhitov R (2017) Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science 356(6337):513–519PubMedGoogle Scholar
  72. 72.
    Nagy C, Haschemi A (2015) Time and demand are two critical dimensions of immunometabolism: the process of macrophage activation and the pentose phosphate pathway. Front Immunol 6:164.  https://doi.org/10.3389/fimmu.2015.00164 CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Borregaard N (2010) Neutrophils, from marrow to microbes. Immunity 33(5):657–670PubMedGoogle Scholar
  74. 74.
    Thompson AA, Binham J, Plant T, Whyte MK, Walmsley SR (2013) Hypoxia, the HIF pathway and neutrophilic inflammatory responses. Biol Chem 394(4):471–477PubMedGoogle Scholar
  75. 75.
    Harris AJ, Thompson AR, Whyte MK, Walmsley SR (2014) HIF-mediated innate immune responses: cell signaling and therapeutic implications. Hypoxia (Auckland, NZ) 2:47–58Google Scholar
  76. 76.
    Mantovani A, Cassatella MA, Costantini C, Jaillon S (2011) Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 11(8):519–531PubMedGoogle Scholar
  77. 77.
    Colotta F, Re F, Polentarutti N, Sozzani S, Mantovani A (1992) Modulation of granulocyte survival and programmed cell death by cytokines and bacterial products. Blood 80(8):2012–2020PubMedGoogle Scholar
  78. 78.
    Walmsley SR, Print C, Farahi N, Peyssonnaux C, Johnson RS, Cramer T, Sobolewski A, Condliffe AM, Cowburn AS, Johnson N, Chilvers ER (2005) Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity. J Exp Med 201(1):105–115PubMedPubMedCentralGoogle Scholar
  79. 79.
    D'Ignazio L, Bandarra D, Rocha S (2016) NF-κB and HIF crosstalk in immune responses. FEBS J 283(3):413–424PubMedGoogle Scholar
  80. 80.
    Vissers MC, Wilkie RP (2007) Ascorbate deficiency results in impaired neutrophil apoptosis and clearance and is associated with up-regulation of hypoxia-inducible factor 1alpha. J Leukoc Biol 81(5):1236–1244PubMedGoogle Scholar
  81. 81.
    Padayatty SJ, Katz A, Wang Y, Eck P, Kwon O, Lee JH, Chen S, Corpe C, Dutta A, Dutta SK, Levine M (2003) Vitamin C as an antioxidant: evaluation of its role in disease prevention. J Am Coll Nutr 22(1):18–35PubMedGoogle Scholar
  82. 82.
    Walmsley SR, Cowburn AS, Clatworthy MR, Morrell NW, Roper EC, Singleton V, Maxwell P, Whyte MK, Chilvers ER (2006) Neutrophils from patients with heterozygous germline mutations in the von Hippel-Lindau protein (pVHL) display delayed apoptosis and enhanced bacterial phagocytosis. Blood 108(9):3176–3178PubMedGoogle Scholar
  83. 83.
    Borregaard N, Herlin T (1982) Energy metabolism of human neutrophils during phagocytosis. J Clin Invest 70(3):550–557PubMedPubMedCentralGoogle Scholar
  84. 84.
    Sadiku P, Willson JA, Dickinson RS, Murphy F, Harris AJ, Lewis A, Sammut D, Mirchandani AS, Ryan E, Watts ER, Thompson AAR, Marriott HM, Dockrell DH, Taylor CT, Schneider M, Maxwell PH, Chilvers ER, Mazzone M, Moral V, Pugh CW, Ratcliffe PJ, Schofield CJ, Ghesquiere B, Carmeliet P, Whyte MK, Walmsley SR (2017) Prolyl hydroxylase 2 inactivation enhances glycogen storage and promotes excessive neutrophilic responses. J Clin Invest 127(9):3407–3420PubMedPubMedCentralGoogle Scholar
  85. 85.
    Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A (2004) Neutrophil extracellular traps kill bacteria. Science 303(5663):1532–1535PubMedGoogle Scholar
  86. 86.
    McInturff AM, Cody MJ, Elliott EA, Glenn JW, Rowley JW, Rondina MT, Yost CC (2012) Mammalian target of rapamycin regulates neutrophil extracellular trap formation via induction of hypoxia-inducible factor 1alpha. Blood 120(15):3118–3125PubMedPubMedCentralGoogle Scholar
  87. 87.
    Vollger L, Akong-Moore K, Cox L, Goldmann O, Wang Y, Schafer ST, Naim HY, Nizet V, von Kockritz-Blickwede M (2016) Iron-chelating agent desferrioxamine stimulates formation of neutrophil extracellular traps (NETs) in human blood-derived neutrophils. Biosci Rep 36(3):e00333PubMedPubMedCentralGoogle Scholar
  88. 88.
    Rodriguez-Espinosa O, Rojas-Espinosa O, Moreno-Altamirano MM, Lopez-Villegas EO, Sanchez-Garcia FJ (2015) Metabolic requirements for neutrophil extracellular traps formation. Immunology 145(2):213–224PubMedPubMedCentralGoogle Scholar
  89. 89.
    Elks PM, Renshaw SA, Meijer AH, Walmsley SR, van Eeden FJ (2015) Exploring the HIFs, buts and maybes of hypoxia signalling in disease: lessons from zebrafish models. Dis Model Mech 8(11):1349–1360PubMedPubMedCentralGoogle Scholar
  90. 90.
    Elks PM, Brizee S, van der Vaart M, Walmsley SR, van Eeden FJ, Renshaw SA, Meijer AH (2013) Hypoxia inducible factor signaling modulates susceptibility to mycobacterial infection via a nitric oxide dependent mechanism. PLoS Pathog 9(12):e1003789.  https://doi.org/10.1371/journal.ppat.1003789 CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Harvie EA, Huttenlocher A (2015) Neutrophils in host defense: new insights from zebrafish. J Leukoc Biol 98(4):523–537PubMedPubMedCentralGoogle Scholar
  92. 92.
    Thompson AA, Dickinson RS, Murphy F, Thomson JP, Marriott HM, Tavares A, Willson J, Williams L, Lewis A, Mirchandani A, Dos Santos Coelho P, Doherty C, Ryan E, Watts E, Morton NM, Forbes S, Stimson RH, Hameed AG, Arnold N, Preston JA, Lawrie A, Finisguerra V, Mazzone M, Sadiku P, Goveia J, Taverna F, Carmeliet P, Foster SJ, Chilvers ER, Cowburn AS, Dockrell DH, Johnson RS, Meehan RR, Whyte MK, Walmsley SR (2017) Hypoxia determines survival outcomes of bacterial infection through HIF-1alpha dependent re-programming of leukocyte metabolism. Sci Immunol 2(8):eaal2861PubMedPubMedCentralGoogle Scholar
  93. 93.
    Azevedo EP, Rochael NC, Guimaraes-Costa AB, de Souza-Vieira TS, Ganilho J, Saraiva EM, Palhano FL, Foguel D (2015) A metabolic shift toward pentose phosphate pathway is necessary for amyloid fibril- and phorbol 12-myristate 13-acetate-induced neutrophil extracellular trap (NET) formation. J Biol Chem 290(36):22174–22183PubMedPubMedCentralGoogle Scholar
  94. 94.
    Zhou W, Cao L, Jeffries J, Zhu X, Staiger CJ, Deng Q (2018) Neutrophil-specific knockout demonstrates a role for mitochondria in regulating neutrophil motility in zebrafish. Dis Model Mech 11(3):dmm033027PubMedPubMedCentralGoogle Scholar
  95. 95.
    Ablain J, Durand EM, Yang S, Zhou Y, Zon LI (2015) A CRISPR/Cas9 vector system for tissue-specific gene disruption in zebrafish. Dev Cell 32(6):756–764PubMedPubMedCentralGoogle Scholar
  96. 96.
    Hasenberg A, Hasenberg M, Mann L, Neumann F, Borkenstein L, Stecher M, Kraus A, Engel DR, Klingberg A, Seddigh P, Abdullah Z, Klebow S, Engelmann S, Reinhold A, Brandau S, Seeling M, Waisman A, Schraven B, Gothert JR, Nimmerjahn F, Gunzer M (2015) Catchup: a mouse model for imaging-based tracking and modulation of neutrophil granulocytes. Nat Methods 12(5):445–452PubMedGoogle Scholar
  97. 97.
    Mildner A, Jung S (2014) Development and function of dendritic cell subsets. Immunity 40(5):642–656PubMedGoogle Scholar
  98. 98.
    Kohler T, Reizis B, Johnson RS, Weighardt H, Forster I (2012) Influence of hypoxia-inducible factor 1alpha on dendritic cell differentiation and migration. Eur J Immunol 42(5):1226–1236PubMedGoogle Scholar
  99. 99.
    Ricciardi A, Elia AR, Cappello P, Puppo M, Vanni C, Fardin P, Eva A, Munroe D, Wu X, Giovarelli M, Varesio L (2008) Transcriptome of hypoxic immature dendritic cells: modulation of chemokine/receptor expression. Mol Cancer Res 6(2):175–185PubMedGoogle Scholar
  100. 100.
    Guak H, Al Habyan S, Ma EH, Aldossary H, Al-Masri M, Won SY, Ying T, Fixman ED, Jones RG, McCaffrey LM, Krawczyk CM (2018) Glycolytic metabolism is essential for CCR7 oligomerization and dendritic cell migration. Nat Commun 9(1):2463PubMedPubMedCentralGoogle Scholar
  101. 101.
    Jantsch J, Chakravortty D, Turza N, Prechtel AT, Buchholz B, Gerlach RG, Volke M, Glasner J, Warnecke C, Wiesener MS, Eckardt KU, Steinkasserer A, Hensel M, Willam C (2008) Hypoxia and hypoxia-inducible factor-1alpha modulate lipopolysaccharide-induced dendritic cell activation and function. J Immunol 180(7):4697–4705PubMedGoogle Scholar
  102. 102.
    Siegert I, Schodel J, Nairz M, Schatz V, Dettmer K, Dick C, Kalucka J, Franke K, Ehrenschwender M, Schley G, Beneke A, Sutter J, Moll M, Hellerbrand C, Wielockx B, Katschinski DM, Lang R, Galy B, Hentze MW, Koivunen P, Oefner PJ, Bogdan C, Weiss G, Willam C, Jantsch J (2015) Ferritin-mediated Iron sequestration stabilizes hypoxia-inducible factor-1alpha upon LPS activation in the presence of ample oxygen. Cell Rep 13(10):2048–2055PubMedGoogle Scholar
  103. 103.
    Pearce EJ, Everts B (2015) Dendritic cell metabolism. Nat Rev Immunol 15(1):18–29PubMedPubMedCentralGoogle Scholar
  104. 104.
    Krawczyk CM, Holowka T, Sun J, Blagih J, Amiel E, DeBerardinis RJ, Cross JR, Jung E, Thompson CB, Jones RG, Pearce EJ (2010) Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 115(23):4742–4749PubMedPubMedCentralGoogle Scholar
  105. 105.
    Everts B, Amiel E, van der Windt GJ, Freitas TC, Chott R, Yarasheski KE, Pearce EL, Pearce EJ (2012) Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells. Blood 120(7):1422–1431PubMedPubMedCentralGoogle Scholar
  106. 106.
    Perrin-Cocon L, Aublin-Gex A, Diaz O, Ramiere C, Peri F, Andre P, Lotteau V (2018) Toll-like receptor 4-induced glycolytic burst in human monocyte-derived dendritic cells results from p38-dependent stabilization of HIF-1alpha and increased hexokinase II expression. J Immunol 201(5):1510–1521PubMedGoogle Scholar
  107. 107.
    Xiong Y, Lingrel JB, Wuthrich M, Klein BS, Vasudevan NT, Jain MK, George M, Deepe GS, Jr. (2016) Transcription factor KLF2 in dendritic cells downregulates Th2 programming via the HIF-1alpha/Jagged2/notch Axis. mBio 7 (3). doi: https://doi.org/10.1128/mBio.00436-16
  108. 108.
    Hammami A, Abidin BM, Heinonen KM, Stager S (2018) HIF-1alpha hampers dendritic cell function and Th1 generation during chronic visceral leishmaniasis. Sci Rep 8(1):3500PubMedPubMedCentralGoogle Scholar
  109. 109.
    Liu G, Bi Y, Xue L, Zhang Y, Yang H, Chen X, Lu Y, Zhang Z, Liu H, Wang X, Wang R, Chu Y, Yang R (2015) Dendritic cell SIRT1-HIF1alpha axis programs the differentiation of CD4+ T cells through IL-12 and TGF-beta1. Proc Natl Acad Sci U S A 112(9):E957–E965PubMedPubMedCentralGoogle Scholar
  110. 110.
    Yamada A, Arakaki R, Saito M, Tsunematsu T, Kudo Y, Ishimaru N (2016) Role of regulatory T cell in the pathogenesis of inflammatory bowel disease. World J Gastroenterol 22(7):2195–2205PubMedPubMedCentralGoogle Scholar
  111. 111.
    Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR, Belkaid Y (2007) Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med 204(8):1775–1785PubMedPubMedCentralGoogle Scholar
  112. 112.
    Fluck K, Breves G, Fandrey J, Winning S (2016) Hypoxia-inducible factor 1 in dendritic cells is crucial for the activation of protective regulatory T cells in murine colitis. Mucosal Immunol 9(2):379–390PubMedGoogle Scholar
  113. 113.
    Koelwyn GJ, Corr EM, Erbay E, Moore KJ (2018) Regulation of macrophage immunometabolism in atherosclerosis. Nat Immunol 19(6):526–537PubMedGoogle Scholar
  114. 114.
    Jiang G, Li T, Qiu Y, Rui Y, Chen W, Lou Y (2007) RNA interference for HIF-1alpha inhibits foam cells formation in vitro. Eur J Pharmacol 562(3):183–190PubMedGoogle Scholar
  115. 115.
    Pedersen SF, Graebe M, Hag AM, Hojgaard L, Sillesen H, Kjaer A (2013) (18)F-FDG imaging of human atherosclerotic carotid plaques reflects gene expression of the key hypoxia marker HIF-1alpha. Am J Nucl Med Mol Imaging 3(5):384–392PubMedPubMedCentralGoogle Scholar
  116. 116.
    Crucet M, Wust SJ, Spielmann P, Luscher TF, Wenger RH, Matter CM (2013) Hypoxia enhances lipid uptake in macrophages: role of the scavenger receptors Lox1, SRA, and CD36. Atherosclerosis 229(1):110–117PubMedGoogle Scholar
  117. 117.
    Tawakol A, Singh P, Mojena M, Pimentel-Santillana M, Emami H, MacNabb M, Rudd JH, Narula J, Enriquez JA, Traves PG, Fernandez-Velasco M, Bartrons R, Martin-Sanz P, Fayad ZA, Tejedor A, Bosca L (2015) HIF-1alpha and PFKFB3 mediate a tight relationship between proinflammatory activation and anerobic metabolism in atherosclerotic macrophages. Arterioscler Thromb Vasc Biol 35(6):1463–1471PubMedPubMedCentralGoogle Scholar
  118. 118.
    Parathath S, Mick SL, Feig JE, Joaquin V, Grauer L, Habiel DM, Gassmann M, Gardner LB, Fisher EA (2011) Hypoxia is present in murine atherosclerotic plaques and has multiple adverse effects on macrophage lipid metabolism. Circ Res 109(10):1141–1152PubMedPubMedCentralGoogle Scholar
  119. 119.
    Folco EJ, Sukhova GK, Quillard T, Libby P (2014) Moderate hypoxia potentiates interleukin-1beta production in activated human macrophages. Circ Res 115(10):875–883PubMedPubMedCentralGoogle Scholar
  120. 120.
    Jain T, Nikolopoulou EA, Xu Q, Qu A (2018) Hypoxia inducible factor as a therapeutic target for atherosclerosis. Pharmacol Ther 183:22–33PubMedGoogle Scholar
  121. 121.
    Asplund A, Friden V, Stillemark-Billton P, Camejo G, Bondjers G (2011) Macrophages exposed to hypoxia secrete proteoglycans for which LDL has higher affinity. Atherosclerosis 215(1):77–81PubMedGoogle Scholar
  122. 122.
    Asplund A, Stillemark-Billton P, Larsson E, Rydberg EK, Moses J, Hulten LM, Fagerberg B, Camejo G, Bondjers G (2010) Hypoxic regulation of secreted proteoglycans in macrophages. Glycobiology 20(1):33–40PubMedGoogle Scholar
  123. 123.
    Aarup A, Pedersen TX, Junker N, Christoffersen C, Bartels ED, Madsen M, Nielsen CH, Nielsen LB (2016) Hypoxia-inducible factor-1alpha expression in macrophages promotes development of atherosclerosis. Arterioscler Thromb Vasc Biol 36(9):1782–1790PubMedGoogle Scholar
  124. 124.
    Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW, Jr. (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112 (12):1796–1808.PubMedPubMedCentralGoogle Scholar
  125. 125.
    Fujisaka S, Usui I, Ikutani M, Aminuddin A, Takikawa A, Tsuneyama K, Mahmood A, Goda N, Nagai Y, Takatsu K, Tobe K (2013) Adipose tissue hypoxia induces inflammatory M1 polarity of macrophages in an HIF-1alpha-dependent and HIF-1alpha-independent manner in obese mice. Diabetologia 56(6):1403–1412PubMedGoogle Scholar
  126. 126.
    Marsch E, Theelen TL, Demandt JA, Jeurissen M, van Gink M, Verjans R, Janssen A, Cleutjens JP, Meex SJ, Donners MM, Haenen GR, Schalkwijk CG, Dubois LJ, Lambin P, Mallat Z, Gijbels MJ, Heemskerk JW, Fisher EA, Biessen EA, Janssen BJ, Daemen MJ, Sluimer JC (2014) Reversal of hypoxia in murine atherosclerosis prevents necrotic core expansion by enhancing efferocytosis. Arterioscler Thromb Vasc Biol 34(12):2545–2553PubMedGoogle Scholar
  127. 127.
    Bhandari T, Nizet V (2014) Hypoxia-inducible factor (HIF) as a pharmacological target for prevention and treatment of infectious diseases. Infect Dis Ther 3(2):159–174PubMedPubMedCentralGoogle Scholar
  128. 128.
    Joharapurkar AA, Pandya VB, Patel VJ, Desai RC, Jain MR (2018) Prolyl hydroxylase inhibitors: a breakthrough in the therapy of anemia associated with chronic diseases. J Med Chem 61(16):6964–6982PubMedGoogle Scholar
  129. 129.
    Sugahara M, Tanaka T, Nangaku M (2017) Prolyl hydroxylase domain inhibitors as a novel therapeutic approach against anemia in chronic kidney disease. Kidney Int 92(2):306–312PubMedGoogle Scholar
  130. 130.
    Harbarth S, Balkhy HH, Goossens H, Jarlier V, Kluytmans J, Laxminarayan R, Saam M, Van Belkum A, Pittet D (2015) Antimicrobial resistance: one world, one fight! Antimicrob Resist Infect Control 4(1):49PubMedCentralGoogle Scholar
  131. 131.
    Rahtu-Korpela L, Maatta J, Dimova EY, Horkko S, Gylling H, Walkinshaw G, Hakkola J, Kivirikko KI, Myllyharju J, Serpi R, Koivunen P (2016) Hypoxia-inducible factor prolyl 4-hydroxylase-2 inhibition protects against development of atherosclerosis. Arterioscler Thromb Vasc Biol 36(4):608–617PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • C. L. Stothers
    • 1
    Email author
  • L. Luan
    • 2
  • B. A. Fensterheim
    • 1
  • J. K. Bohannon
    • 2
  1. 1.Department of Pathology, Microbiology, and ImmunologyVanderbilt University School of MedicineNashvilleUSA
  2. 2.Department of AnesthesiologyVanderbilt University Medical CenterNashvilleUSA

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