Role of Hypoxia-inducible factor 1 alpha in host defense during pneumococcal pneumonia

Hypoxia-inducible factor (HIF)1 alpha is a transcription factor involved in cellular metabolism and regulation of immune cell effector functions. Here, we studied the role of HIF1 alpha in myeloid cells during pneumonia caused by the major causative pathogen, Streptococcus pneumoniae (Spneu). Mice deficient for HIF1 alpha in myeloid cells (LysM(cre)Hif1 alpha(fl)(/)(fl)) were generated to study the in vitro responsiveness of bone marrow-derived macrophages (BMDMs) and alveolar macrophages (AMs) to the Gram-positive bacterial wall component lipoteichoic acid (LTA) and heat-killed Spneu, and the in vivo host response after infection with Spneu via the airways. Both BMDMs and AMs released more lactate upon stimulation with LTA or Spneu, indicative of enhanced glycolysis; HIF1 alpha-deficiency in these cells was associated with diminished lactate release. In BMDMs, HIF1 alpha-deficiency resulted in reduced secretion of tumor necrosis factor (TNF)alpha and interleukin (IL)-6 upon activation with Spneu but not LTA, while HIF1 alpha-deficient AMs secreted less TNF alpha and IL-6 in response to LTA, and TNF alpha after Spneu stimulation. However, no difference was found in the host response of LysM(cre)Hif1 alpha(fl)(/)(fl) mice after Spneu infection as compared to controls. Similar in vivo findings were obtained in neutrophil (Mrp8(cre)Hif1 alpha(fl)(/)(fl)) HIF1 alpha-deficient mice. These data suggest that myeloid HIF1 alpha is dispensable for the host defense during pneumococcal pneumonia. HIF1 alpha is involved in cytokine production and glycolysis in myeloid cells, but its role is dispensable during the host response against pneumococcal pneumonia.