HIF-1alpha Expression Regulates the Bactericidal Capacity of Phagocytes

J Clin Invest. 2005 Jul;115(7):1806-15. doi: 10.1172/JCI23865.

Abstract

Hypoxia is a characteristic feature of the tissue microenvironment during bacterial infection. Here we report on our use of conditional gene targeting to examine the contribution of hypoxia-inducible factor 1, alpha subunit (HIF-1alpha) to myeloid cell innate immune function. HIF-1alpha was induced by bacterial infection, even under normoxia, and regulated the production of key immune effector molecules, including granule proteases, antimicrobial peptides, nitric oxide, and TNF-alpha. Mice lacking HIF-1alpha in their myeloid cell lineage showed decreased bactericidal activity and failed to restrict systemic spread of infection from an initial tissue focus. Conversely, activation of the HIF-1alpha pathway through deletion of von Hippel-Lindau tumor-suppressor protein or pharmacologic inducers supported myeloid cell production of defense factors and improved bactericidal capacity. HIF-1alpha control of myeloid cell activity in infected tissues could represent a novel therapeutic target for enhancing host defense.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antimicrobial Cationic Peptides / biosynthesis
  • Bacteria / immunology*
  • Bacterial Infections / genetics
  • Bacterial Infections / immunology
  • Bacterial Infections / pathology
  • Gene Expression Regulation
  • Gene Targeting
  • Hypoxia / genetics
  • Hypoxia / immunology
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Immunity, Innate
  • In Vitro Techniques
  • Mice
  • Mice, Knockout
  • Peptide Hydrolases / biosynthesis
  • Phagocytes / immunology*
  • Phagocytes / pathology
  • Streptococcal Infections / immunology
  • Streptococcus pyogenes
  • Transcription Factors / deficiency
  • Transcription Factors / genetics*
  • Transcription Factors / physiology*

Substances

  • Antimicrobial Cationic Peptides
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Transcription Factors
  • Peptide Hydrolases