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 is not critical for neutrophil endothelial transcytosis or oxidat...
HIF-1α is not critical for neutrophil endothelial transcytosis or oxidative burst function. (A) Hypoxia is present in lesions generated by GAS infection. Immunostaining for hypoxic markers in WT mouse skin upon GAS infection. Magnification, ×100 (top); ×200 (bottom). The control corresponds to the omission of primary antibody. (B) Similar numbers of neutrophils in WT and HIF-1α–null mouse skin tissue observed by immunostaining at 6, 12, and 24 hours after infection. Magnification, ×100. (C) Migratory capacity of activated neutrophils across endothelium is not affected by the deletion of HIF-1α. Count of neutrophils transcytosing pulmonary endothelial monolayer toward GAS or fMLP stimulus is shown. (D) HIF-1α activity does not affect oxidative burst capacity. Flow cytometry of leukocytes derived from WT (squares), HIF-1α–null (triangles) and vHL-null (inverted triangles) mice. Oxidative burst capacity as measured by fluorescence before (0 seconds) and after the addition of a reagent designed to stimulate leukocyte phagocytic and oxidative activity as described in Methods. Data are representative of the results obtained for 4 individuals per genotype.