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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Figure 3

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HIF-1α deletion renders mice more susceptible to GAS infection. (A) Area...
HIF-1α deletion renders mice more susceptible to GAS infection. (A) Area of necrotic ulcer and (B) loss of weight in individual WT (squares) and HIF-1α myeloid–null mice (triangles) 4 days after infection with GAS. (C) Representative appearance of GAS-induced necrotic skin ulcers in WT and HIF-1α myeloid–null mice. A total of 11 mice in each group were tested in 3 paired experiments. (D) Bacterial counts in the blood, spleen, and skin of WT and HIF-1α myeloid–null mice infected with GAS. The fold difference in quantitive GAS culture between WT and HIF-1α–null animals is annotated. Statistical analyses were performed using unpaired Student’s t test. *P < 0.05; **P < 0.01.