Hypoxia-inducible factor- (HIF-) 1α has been implicated in the ability of cells to adapt to alterations in oxygen levels. Bacterial stimuli can induce HIF1α in immune cells, including those of myeloid origin. We here determined the role of myeloid cell HIF1α in the host response during pneumonia and sepsis caused by the common human pathogen Klebsiella pneumoniae. To this end, we generated mice deficient for HIF1α 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, HIF1α-deficient mice had increased bacterial loads in the lungs and distant organs after infection as compared to control mice, pointing at a role for HIF1α in macrophages. Myeloid HIF1α-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 HIF1α presence. These data suggest a role for HIF1α expressed in lung macrophages in protective innate immunity during pneumonia caused by a common bacterial pathogen.

中文翻译：

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巨噬细胞中的缺氧诱导因子 1α 对肺炎克雷伯菌引起的肺炎败血症的宿主防御很重要，但在嗜中性粒细胞中则不然

缺氧诱导因子 (HIF-) 1 α与细胞适应氧水平变化的能力有关。细菌刺激可以在免疫细胞中诱导 HIF1α ，包括骨髓来源的细胞。我们在这里确定了骨髓细胞 HIF1 α在由常见人类病原体肺炎克雷伯菌引起的肺炎和败血症期间宿主反应中的作用。为此，我们产生了骨髓细胞（LysM-cre × Hif1α ^fl/fl）或中性粒细胞（Mrp8-cre × Hif1α ^{fl/fl ）中缺乏}HIF1α的小鼠，并通过气道用肺炎克雷伯菌感染这些小鼠。骨髓，但不是中性粒细胞，HIF1 α与对照小鼠相比，缺陷小鼠在感染后肺部和远处器官中的细菌负荷增加，这表明 HIF1 α在巨噬细胞中的作用。骨髓 HIF1 α缺陷小鼠在静脉感染后没有表现出增加的细菌生长，这表明它们在肺炎期间的表型是由肺巨噬细胞介导的。来自 LysM-cre × Hif1α ^fl/fl小鼠的肺泡和肺间质巨噬细胞在克雷伯氏菌刺激下产生较低量的免疫增强细胞因子肿瘤坏死因子，而它们吞噬或产生活性氧的能力没有改变。无论 HIF1 α是否存在，肺泡巨噬细胞都不会上调响应脂多糖的糖酵解。这些数据表明，在由常见细菌病原体引起的肺炎期间，肺巨噬细胞中表达的 HIF1 α在保护性先天免疫中的作用。