HIF-1α expression regulates the bactericidal capacity of phagocytes
Carole Peyssonnaux, Vivekanand Datta, Thorsten Cramer, Andrew Doedens, Emmanuel A. Theodorakis, Richard L. Gallo, Nancy Hurtado-Ziola, Victor Nizet, Randall S. Johnson
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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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 and vHL regulate NO production. (A) Total RNA from WT, HIF-1α–/–,...
HIF-1α and vHL regulate NO production. (A) Total RNA from WT, HIF-1α–/–, and vHL–/– bone marrow–derived macrophages infected with GAS isolated 3 hours after antibiotic treatment. iNOS mRNA was quantified by RT-PCR. WT, nonstimulated macrophages were arbitrarily set to 1 unit following normalization to ribosomal RNA levels. (B) NO production under GAS stimulation ± 1.5 mM AG (1-amino-2-hydroxyguanidine, p-toluenesulfate; Calbiochem). BM-derived macrophages were cultured for 20 hours, conditioned supernatant collected, and NO protein levels measured by the Griess assay. (C) Mim enhances iNOS expression of WT macrophages stimulated by GAS. Total RNA from WT and HIF-1α–null BM-derived macrophages infected with GAS ± Mim isolated 3 hours after antibiotic treatment. iNOS mRNA was quantified by RT-PCR. WT, noninfected macrophages were arbitrarily set to 1 unit following normalization to ribosomal RNA levels. Statistical analyses performed by unpaired Student’s t test. **P < 0.01; ***P < 0.001. (D) Inhibition of iNOS by AG blunts observed differences between HIF-1α–null and WT microbicidal activity. (E) Inhibition of iNOS prevents GAS-induced HIF-1α expression. Expression of HIF-1α is normalized to β-actin levels.