Pereverzeva Liza, Otto Natasja A, Peters-Sengers Hessel, Roelofs Joris J T H, de Vos Alex F, van der Poll Tom
Center of Experimental & Molecular Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
Amsterdam Infection & Immunity Institute, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
Pathog Dis. 2023 Jan 17;81. doi: 10.1093/femspd/ftac047.
Hypoxia-inducible factor (HIF)1α is a transcription factor involved in cellular metabolism and regulation of immune cell effector functions. Here, we studied the role of HIF1α in myeloid cells during pneumonia caused by the major causative pathogen, Streptococcus pneumoniae (Spneu). Mice deficient for HIF1α in myeloid cells (LysMcreHif1αfl/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; HIF1α-deficiency in these cells was associated with diminished lactate release. In BMDMs, HIF1α-deficiency resulted in reduced secretion of tumor necrosis factor (TNF)α and interleukin (IL)-6 upon activation with Spneu but not LTA, while HIF1α-deficient AMs secreted less TNFα and IL-6 in response to LTA, and TNFα after Spneu stimulation. However, no difference was found in the host response of LysMcreHif1αfl/fl mice after Spneu infection as compared to controls. Similar in vivo findings were obtained in neutrophil (Mrp8creHif1αfl/fl) HIF1α-deficient mice. These data suggest that myeloid HIF1α is dispensable for the host defense during pneumococcal pneumonia.
缺氧诱导因子（HIF）1α是一种参与细胞代谢和免疫细胞效应功能调节的转录因子。在此，我们研究了HIF1α在由主要致病病原体肺炎链球菌（Spneu）引起的肺炎期间在髓样细胞中的作用。构建了髓样细胞中HIF1α缺陷的小鼠（LysMcreHif1αfl/fl），以研究骨髓来源的巨噬细胞（BMDM）和肺泡巨噬细胞（AM）对革兰氏阳性菌细胞壁成分脂磷壁酸（LTA）和热灭活的Spneu的体外反应，以及经气道感染Spneu后的体内宿主反应。用LTA或Spneu刺激后，BMDM和AM释放的乳酸都更多，这表明糖酵解增强；这些细胞中HIF1α的缺陷与乳酸释放减少有关。在BMDM中，HIF1α缺陷导致用Spneu而非LTA激活后肿瘤坏死因子（TNF）α和白细胞介素（IL）-6的分泌减少，而HIF1α缺陷的AM对LTA刺激分泌的TNFα和IL-6较少，对Spneu刺激分泌的TNFα也较少。然而，与对照组相比，LysMcreHif1αfl/fl小鼠在感染Spneu后的宿主反应没有差异。在中性粒细胞（Mrp8creHif1αfl/fl）HIF1α缺陷的小鼠中也获得了类似的体内研究结果。这些数据表明，在肺炎球菌肺炎期间，髓样HIF1α对宿主防御并非必需。
