Myeloid HIF-1α couples glycolytic energy supply with NCF2-dependent oxidative killing to protect against Klebsiella pneumoniae pneumonia

作者：Guo Y, Meng B, Zhu R, Dong S, Zhang S, Wang J, Li Y, Yang Y, Liu Y, Yu L, Li J · 发表于：Free radical biology & medicine · 年份：2026 · DOI：10.1016/j.freeradbiomed.2026.06.058 · 研究领域：Hypoxia-Inducible Factor 1, alpha Subunit、Klebsiella pneumoniae、Klebsiella Infections、NADPH Oxidases、Animals、Glycolysis、Mice、Humans、Mice, Knockout、Phagocytosis、Reactive Oxygen Species、Signal Transduction

BACKGROUND: Hypervirulent Klebsiella pneumoniae (hvKp) induces severe pneumonia and sepsis. HIF-1α coordinates metabolic and immune responses in myeloid cells, but its role in hvKp-mediated pulmonary defense remains undefined. METHODS: Monocyte HIF-1α expression was assessed in patients with Klebsiella pneumoniae (K. pneumoniae) pneumonia. Myeloid-specific Hif-1α knockout mice and BMDMs were used to examine survival, bacterial burden, and macrophage function. RNA-seq, Seahorse flux analysis, and confocal microscopy were employed to investigate the regulatory effects of HIF-1α on phagocytosis and ROS production. The Hif-1α-NCF2-ROS signaling pathway was substantiated through the application of small interfering RNA (siRNA), JASPAR prediction tools, dual-luciferase reporter assays, chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR), metabolic inhibitors, and dimethyloxalylglycine (DMOG), a prolyl hydroxylase inhibitor that stabilizes HIF-1α. RESULTS: Clinical data showed a negative correlation between monocyte HIF-1α levels and serum CRP, procalcitonin, ICU stay duration, and SOFA scores. In vivo, myeloid Hif-1α knockout mice demonstrated heightened susceptibility to hvKp, with markedly reduced survival and widespread bacterial dissemination. Mechanistically, Hif-1α-deficient macrophages displayed impaired phagocytosis, phagolysosomal maturation, and glycolytic reprogramming in response to infection. RNA-seq identified NCF2, encoding p67-phox, as a critica...