Hypoxia‐Inducible Factor‐1α in Macrophages, but Not in Neutrophils, Is Important for Host Defense during Klebsiella pneumoniae‐Induced Pneumosepsis

Hypoxia‐inducible factor‐ (HIF‐) 1 α has been implicated in the ability of cells to adapt to alterations in oxygen levels. Bacterial stimuli can induce HIF1 α in immune cells, including those of myeloid origin. We here determined the role of myeloid cell HIF1 α in the host response during pneumonia and sepsis caused by the common human pathogen Klebsiella pneumoniae . To this end, we generated mice deficient for HIF1 α in myeloid cells (LysM‐cre × Hif1α fl/fl ) or neutrophils (Mrp8‐cre × Hif1α fl/fl ) and infected these with Klebsiella pneumoniae via the airways. Myeloid, but not neutrophil, HIF1 α ‐deficient mice had increased bacterial loads in the lungs and distant organs after infection as compared to control mice, pointing at a role for HIF1 α in macrophages. Myeloid HIF1 α ‐deficient mice did not show increased bacterial growth after intravenous infection, suggesting that their phenotype during pneumonia was mediated by lung macrophages. Alveolar and lung interstitial macrophages from LysM‐cre × Hif1α fl/fl mice produced lower amounts of the immune enhancing cytokine tumor necrosis factor upon stimulation with Klebsiella , while their capacity to phagocytose or to produce reactive oxygen species was unaltered. Alveolar macrophages did not upregulate glycolysis in response to lipopolysaccharide, irrespective of HIF1 α presence. These data suggest a role for HIF1 α expressed in lung macrophages in protective innate immunity during pneumonia caused by a common bacterial pathogen.