Hypoxia-Inducible Factor-1 in Macrophages, but Not in Neutrophils, Is Important for Host Defense during -Induced Pneumosepsis.

Hypoxia-inducible factor- (HIF-) 1 has been implicated in the ability of cells to adapt to alterations in oxygen levels. Bacterial stimuli can induce HIF1 in immune cells, including those of myeloid origin. We here determined the role of myeloid cell HIF1 in the host response during pneumonia and sepsis caused by the common human pathogen . To this end, we generated mice deficient for HIF1 in myeloid cells (LysM-cre × ) or neutrophils (Mrp8-cre × ) and infected these with via the airways. Myeloid, but not neutrophil, HIF1-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 in macrophages. Myeloid HIF1-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 × mice produced lower amounts of the immune enhancing cytokine tumor necrosis factor upon stimulation with , 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 presence. These data suggest a role for HIF1 expressed in lung macrophages in protective innate immunity during pneumonia caused by a common bacterial pathogen.