HIF-1α expression regulates the bactericidal capacity of phagocytes
Carole Peyssonnaux, … , Victor Nizet, Randall S. Johnson
Carole Peyssonnaux, … , Victor Nizet, Randall S. Johnson
Published July 1, 2005
Citation Information: J Clin Invest. 2005;115(7):1806-1815. https://doi.org/10.1172/JCI23865.
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Research Article Infectious disease

HIF-1α expression regulates the bactericidal capacity of phagocytes

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, α subunit (HIF-1α) to myeloid cell innate immune function. HIF-1α 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-α. Mice lacking HIF-1α 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-1α 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-1α control of myeloid cell activity in infected tissues could represent a novel therapeutic target for enhancing host defense.

Authors

Carole Peyssonnaux, Vivekanand Datta, Thorsten Cramer, Andrew Doedens, Emmanuel A. Theodorakis, Richard L. Gallo, Nancy Hurtado-Ziola, Victor Nizet, Randall S. Johnson

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HIF-1α regulates bactericidal activity of myeloid cells. (A) Intracellul...
HIF-1α regulates bactericidal activity of myeloid cells. (A) Intracellular killing of GAS by WT, HIF-1α–null, or vHL-null macrophages. BM-derived macrophages were inoculated with GAS at an MOI equal to 2.5 and cultured under normoxic (white bars) or hypoxic (0.1%; black bars) conditions for 1 hour after antibiotic treatment. Statistical analyses were performed using unpaired Student’s t test. *P < 0.05; **P < 0.01. (B) Loss of HIF-1α in macrophages decreases intracellular killing of GAS and of P. aeruginosa. WT (black bars) or HIF-1α–null (white bars) BM-derived macrophages were incubated with bacteria for 1 hour before antibiotics were added. Intracellular killing was analyzed by determination of viable CFUs in macrophage lysates at the specified time points after bacterial uptake. Experiments were performed in triplicate. SEM is displayed. Experiment shown is representative of 3 repeated studies. (C) Loss of vHL in BM-derived macrophages increases intracellular killing of GAS and of P. aeruginosa. Experiments were performed in triplicate and are representative of 3 repeated studies. SEM is displayed. (D) Pharmacologic agonists of HIF-1α increase myeloid cell bactericidal activity. Preincubation (5 hours) with desferrioxamine mesylate (DFO), CoCl2, OH-pyridone, or Mim increased the intracellular killing capacity of WT macrophages against GAS. ***P < 0.001.