HIF-1alpha expression regulates the bactericidal capacity of phagocytes.
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.
Peyssonnaux
Carole
C
Division of Biological Sciences, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.
Datta
Vivekanand
V
Cramer
Thorsten
T
Doedens
Andrew
A
Theodorakis
Emmanuel A
EA
Gallo
Richard L
RL
Hurtado-Ziola
Nancy
N
Nizet
Victor
V
Johnson
Randall S
RS
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis; D001419:Bacteria / Q000276:immunology*; D001424:Bacterial Infections / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D018390:Gene Targeting; D000860:Hypoxia / Q000235:genetics / Q000276:immunology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007113:Immunity, Innate; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D010447:Peptide Hydrolases / Q000096:biosynthesis; D010586:Phagocytes / Q000276:immunology* / Q000473:pathology; D013290:Streptococcal Infections / Q000276:immunology; D013297:Streptococcus pyogenes; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*
D023181:Antimicrobial Cationic Peptides; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D010447:Peptide Hydrolases