Home LiteratureArticle Details
PMID: 12628185 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

HIF-1alpha is essential for myeloid cell-mediated inflammation.

Cell ·Vol. 112 ·No. 5 ·2003-03-07 ·Pages 645-57

Cramer T, Yamanishi Y, Clausen BE, Förster I, Pawlinski R, Mackman N, Haase VH, Jaenisch R, Corr M, Nizet V, Firestein GS, Gerber HP, Ferrara N, Johnson RS

Abstract

Granulocytes and monocytes/macrophages of the myeloid lineage are the chief cellular agents of innate immunity. Here, we have examined the inflammatory response in mice with conditional knockouts of the hypoxia responsive transcription factor HIF-1alpha, its negative regulator VHL, and a known downstream target, VEGF. We find that activation of HIF-1alpha is essential for myeloid cell infiltration and activation in vivo through a mechanism independent of VEGF. Loss of VHL leads to a large increase in acute inflammatory responses. Our results show that HIF-1alpha is essential for the regulation of glycolytic capacity in myeloid cells: when HIF-1alpha is absent, the cellular ATP pool is drastically reduced. The metabolic defect results in profound impairment of myeloid cell aggregation, motility, invasiveness, and bacterial killing. This role for HIF-1alpha demonstrates its direct regulation of survival and function in the inflammatory microenvironment.

MeSH Terms
Adenosine Triphosphate/metabolism Animals Arthritis/genetics,immunology Cell Aggregation/genetics Cell Movement/genetics Chemotaxis, Leukocyte/genetics,immunology Endothelial Growth Factors/deficiency,genetics Energy Metabolism/genetics Female Hypoxia/genetics,immunology Hypoxia-Inducible Factor 1, alpha Subunit Immunity/genetics,immunology Inflammation/genetics,immunology Intercellular Signaling Peptides and Proteins/deficiency,genetics Ligases/genetics,immunology Lymphokines/deficiency,genetics Macrophages/immunology,metabolism Male Mice Mice, Knockout Myeloid Cells/immunology,metabolism Neutrophils/immunology,metabolism Phagocytosis/genetics,immunology Transcription Factors/genetics,immunology Tumor Suppressor Proteins Ubiquitin-Protein Ligases Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors Von Hippel-Lindau Tumor Suppressor Protein
Chemicals
Endothelial Growth Factors Hypoxia-Inducible Factor 1, alpha Subunit Intercellular Signaling Peptides and Proteins Lymphokines Transcription Factors Tumor Suppressor Proteins Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors Adenosine Triphosphate Ubiquitin-Protein Ligases Von Hippel-Lindau Tumor Suppressor Protein Ligases
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Cramer Thorsten
Molecular Biology Section, Division of Biological Sciences, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Yamanishi Yuji
Clausen Björn E
Förster Irmgard
Pawlinski Rafal
Mackman Nigel
Haase Volker H
Jaenisch Rudolf
Corr Maripat
Nizet Victor
Firestein Gary S
Gerber Hans Peter
Ferrara Napoleone
Johnson Randall S
References (61)
61 references, click to expand
  1. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis.
    Nature. 1999 May 20;399(6733):271-5 PMID: 10353251
  2. Phagocytes and oxidative stress.
    Am J Med. 2000 Jul;109(1):33-44 PMID: 10936476
  3. 2-Deoxyglucose selectively inhibits Fc and complement receptor-mediated phagocytosis in mouse peritoneal macrophages II. Dissociation of the inhibitory effects of 2-deoxyglucose on phagocytosis and ATP generation.
    J Exp Med. 1976 Dec 1;144(6):1484-93 PMID: 1003099
  4. Targeted disruption of CD43 gene enhances T lymphocyte adhesion.
    J Immunol. 1993 Aug 1;151(3):1528-34 PMID: 8335945
  5. Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology.
    Trends Mol Med. 2001 Aug;7(8):345-50 PMID: 11516994
  6. Leukocyte glycolysis and lactate output in animal sepsis and ex vivo human blood.
    Metabolism. 1999 Jun;48(6):779-85 PMID: 10381154
  7. Regional manifestations and control of the immune system.
    FASEB J. 2002 Jun;16(8):849-56 PMID: 12039867
  8. Biological consequences of tumor hypoxia.
    Semin Oncol. 2001 Apr;28(2 Suppl 8):36-41 PMID: 11395851
  9. The biochemical basis of phagocytosis. I. Metabolic changes during the ingestion of particles by polymorphonuclear leukocytes.
    J Biol Chem. 1959 Jun;234(6):1355-62 PMID: 13654378
  10. HIF-1 and mechanisms of hypoxia sensing.
    Curr Opin Cell Biol. 2001 Apr;13(2):167-71 PMID: 11248550
  11. Bioenergetics of immune functions: fundamental and therapeutic aspects.
    Immunol Today. 2000 Apr;21(4):192-9 PMID: 10740243
  12. Wound healing: the effect of macrophage and tumour derived angiogenesis factors on skin graft vascularization.
    Br J Exp Pathol. 1987 Aug;68(4):569-74 PMID: 2443156
  13. Effects of 2-deoxy-D-glucose on human monocyte metabolism and function.
    J Reticuloendothel Soc. 1980 Oct;28(4):367-79 PMID: 7431370
  14. Expression of HIF-1alpha by human macrophages: implications for the use of macrophages in hypoxia-regulated cancer gene therapy.
    J Pathol. 2002 Feb;196 (2):204-12 PMID: 11793372
  15. Tumor hypoxia, the physiological link between Trousseau's syndrome (carcinoma-induced coagulopathy) and metastasis.
    Cancer Res. 2001 Feb 1;61(3):795-8 PMID: 11221857
  16. Invasion of brain microvascular endothelial cells by group B streptococci.
    Infect Immun. 1997 Dec;65(12):5074-81 PMID: 9393798
  17. Hyperbaric oxygen therapy in acute necrotizing infections. With a special reference to the effects on tissue gas tensions.
    Ann Chir Gynaecol. 2000;89 Suppl 214:7-36 PMID: 11288993
  18. Hypoxia, oxidative stress and rheumatoid arthritis.
    Br Med Bull. 1995 Apr;51(2):419-36 PMID: 7552073
  19. [Determination of glycolysis metabolites in inflamed and non-inflamed paw tissue of rats].
    Med Pharmacol Exp Int J Exp Med. 1967;17 (6):557-75 PMID: 5631691
  20. Granulocytes utilize different energy sources for movement and phagocytosis.
    Inflammation. 1982 Sep;6(3):245-56 PMID: 6813260
  21. Chemotactic factor-induced generation of superoxide radicals by human neutrophils: effect of metabolic inhibitors and antiinflammatory drugs.
    Arthritis Rheum. 1979 Jul;22(7):755-63 PMID: 222300
  22. [The energy situation in the course of acute experimental inflammation].
    Med Pharmacol Exp Int J Exp Med. 1967;16(5):425-31 PMID: 4227796
  23. Measurement of pH and ionic composition of pericellular sites.
    Philos Trans R Soc Lond B Biol Sci. 1975 Jul 17;271(912):261-72 PMID: 239420
  24. From systemic T cell self-reactivity to organ-specific autoimmune disease via immunoglobulins.
    Immunity. 1999 Apr;10(4):451-61 PMID: 10229188
  25. Organ-specific disease provoked by systemic autoimmunity.
    Cell. 1996 Nov 29;87(5):811-22 PMID: 8945509
  26. The von Hippel-Lindau tumor suppressor gene.
    Exp Cell Res. 2001 Mar 10;264(1):117-25 PMID: 11237528
  27. A metabolic comparison between human blood monocytes and neutrophils.
    Adv Exp Med Biol. 1979;121(A):29-36 PMID: 547727
  28. Inflammation and transcutaneous measurement of oxygen pressure in dermatology.
    Adv Exp Med Biol. 1987;220:79-82 PMID: 3673789
  29. Ultrastructural, histological, and biochemical alterations produced by 12-O-tetradecanoyl-phorbol-13-acetate on mouse epidermis and their relevance to skin tumor promotion.
    Cancer Res. 1973 Feb;33(2):269-86 PMID: 4347466
  30. The peritoneal environment during infection. The effect of monomicrobial and polymicrobial bacteria on pO2 and pH.
    Ann Surg. 1991 Mar;213(3):253-60 PMID: 1998406
  31. Hypoxia inhibits macrophage migration.
    Eur J Immunol. 1999 Jul;29(7):2280-7 PMID: 10427991
  32. Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker.
    J Invest Dermatol. 1982 Mar;78(3):206-9 PMID: 6276474
  33. Influence of inhibitors of cellular function on chemotactic factor-induced neutrophil aggregation.
    J Immunol. 1977 Nov;119(5):1751-6 PMID: 915280
  34. Analysis of pH, pO2 and pCO2 in drainage fluid allows for rapid detection of infectious complications during the follow-up period after abdominal surgery.
    Infection. 1994 Nov-Dec;22(6):386-9 PMID: 7698834
  35. HIF-1 alpha is required for solid tumor formation and embryonic vascularization.
    EMBO J. 1998 Jun 1;17(11):3005-15 PMID: 9606183
  36. THE NATURE OF LEUKEMIC BLOOD CELLS AS DETERMINED BY THEIR METABOLISM.
    J Clin Invest. 1939 May;18(3):291-300 PMID: 16694664
  37. VPF/VEGF and the angiogenic response.
    Semin Perinatol. 2000 Feb;24(1):75-8 PMID: 10709865
  38. Macrophage responses to hypoxia: relevance to disease mechanisms.
    J Leukoc Biol. 1999 Dec;66(6):889-900 PMID: 10614769
  39. Arthritis provoked by linked T and B cell recognition of a glycolytic enzyme.
    Science. 1999 Nov 26;286(5445):1732-5 PMID: 10576739
  40. Glycogenolysis versus glucose transport in human granulocytes: differential activation in phagocytosis and chemotaxis.
    Blood. 1982 Oct;60(4):888-93 PMID: 7115957
  41. Resolution of cutaneous inflammation after local elimination of macrophages.
    Nat Biotechnol. 2000 Jan;18(1):48-51 PMID: 10625390
  42. Innate immunity.
    N Engl J Med. 2000 Aug 3;343(5):338-44 PMID: 10922424
  43. The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages.
    Am J Pathol. 2000 Aug;157(2):411-21 PMID: 10934146
  44. Conditional gene targeting in macrophages and granulocytes using LysMcre mice.
    Transgenic Res. 1999 Aug;8(4):265-77 PMID: 10621974
  45. Expression of hypoxia-inducible factor 1alpha by macrophages in the rheumatoid synovium: implications for targeting of therapeutic genes to the inflamed joint.
    Arthritis Rheum. 2001 Jul;44(7):1540-4 PMID: 11465705
  46. Alterations of ambient oxygen tension modulate the expression of tumor necrosis factor and macrophage inflammatory protein-1 alpha from murine alveolar macrophages.
    Am J Respir Cell Mol Biol. 1995 Oct;13(4):399-409 PMID: 7546769
  47. Modulation of leukocyte behavior by an inflamed extracellular matrix.
    Dev Immunol. 2000;7(2-4):227-38 PMID: 11097214
  48. Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1alpha.
    Genes Dev. 2001 Oct 1;15(19):2520-32 PMID: 11581158
  49. Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced increase in vascular permeability in mouse skin by lipoxygenase inhibitors.
    Jpn J Pharmacol. 1985 Jun;38(2):161-8 PMID: 3928951
  50. Hypoxia-inducible factor 1: control of oxygen homeostasis in health and disease.
    Pediatr Res. 2001 May;49(5):614-7 PMID: 11328942
  51. Energy metabolism of human neutrophils during phagocytosis.
    J Clin Invest. 1982 Sep;70(3):550-7 PMID: 7107894
  52. Signaling takes a breath--new quantitative perspectives on bioenergetics and signal transduction.
    Immunity. 2001 Oct;15(4):497-502 PMID: 11672532
  53. Inflammation, glycolytic metabolism, and glycosaminoglycans.
    Exp Pathol. 1986;30(1):1-19 PMID: 3530796
  54. Comparison of synovial PO2 and sympathetic vasoconstrictor responses in normal and acutely inflamed rabbit knee joints.
    Exp Physiol. 1995 Mar;80(2):209-20 PMID: 7786513
  55. 2-Deoxyglucose and inflammation.
    J Pharm Pharmacol. 1966 Mar;18(3):199-200 PMID: 4381222
  56. Tumor-derived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function.
    Cancer Res. 1999 Apr 1;59(7):1592-8 PMID: 10197634
  57. The effect of 2-deoxyglucose on guinea pig polymorphonuclear leukocyte phagocytosis.
    J Cell Physiol. 1977 Apr;91(1):89-102 PMID: 856841
  58. Differences in oxygen metabolism of phagocytosing monocytes and neutrophils.
    J Clin Invest. 1978 Feb;61(2):480-8 PMID: 202614
  59. Regulation of energy metabolism in macrophages during hypoxia. Roles of fructose 2,6-bisphosphate and ribose 1,5-bisphosphate.
    J Biol Chem. 2001 Jul 27;276(30):28554-61 PMID: 11373280
  60. Transcription factor HIF-1 is a necessary mediator of the pasteur effect in mammalian cells.
    Mol Cell Biol. 2001 May;21(10):3436-44 PMID: 11313469
  61. Effect of hypoxia on release of IL-1 and TNF by human alveolar macrophages.
    Am J Respir Cell Mol Biol. 1996 Feb;14(2):170-6 PMID: 8630267
Article Info
Journal
Cell
Abbr.
Cell
ISSN
0092-8674
DOI
10.1016/s0092-8674(03)00154-5
Published
2003-03-07
Pages
645-57
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC4480774
Subset
IM
Grants
NIDDK NIH HHS · K08 DK002668 · United States
NCI NIH HHS · R01 CA082515 · United States
NCI NIH HHS · R01 CA100787 · United States
NCI NIH HHS · CA82515 · United States
Corrections
ErratumIn
-
External Links
PubMed source DOI: 10.1016/s0092-8674(03)00154-5 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2