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<p>Metabolic reprogramming in immune cells can determine the outcome of pathogen infection. For <i>Pseudomonas aeruginosa</i>, a clinically challenging pathogen, it remains unclear whether the host can exploit this strategy to combat bacterial invasion. Here, we identify phosphoglycerate dehydrogenase as a key mediator of macrophage inflammation during <i>Pseudomonas aeruginosa</i> infection. Pharmacological and genetic inhibition of phosphoglycerate dehydrogenase suppress macrophage hyperactivation and the production of pro-inflammatory cytokines. In a murine model of <i>Pseudomonas aeruginosa</i> pneumonia, myeloid-specific deletion of phosphoglycerate dehydrogenase improves survival, alleviates lung injury, and reduces bacterial load. Similarly, dietary restriction of L-serine improves prognosis in infected mice. Mechanistically, phosphoglycerate dehydrogenase fuels L-serine synthesis to augment one-carbon metabolism, which strengthens the direct interaction between histone H3 lysine 27 trimethylation and dual-specificity phosphatase 4. This cascade ultimately promotes extracellular signal-regulated kinase 1/2 phosphorylation. Our study uncovers a metabolism-epigenetics crosstalk that amplifies macrophage inflammation, proposing metabolic modulation as a therapeutic strategy for bacterial pneumonia.</p>

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Phosphoglycerate dehydrogenase-mediated serine reprogramming aggravates macrophage hyperinflammation in murine Pseudomonas aeruginosa pneumonia

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月20日

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  • Rong Chen,
  • Ran Zeng,
  • Mengmeng Shi,
  • Guoliang Zhang,
  • Feiyang Wang,
  • Qingyuan Yang,
  • Yanshan Jiang,
  • Yuxuan Zhang,
  • Yanan Li,
  • Jieming Qu

摘要

Metabolic reprogramming in immune cells can determine the outcome of pathogen infection. For Pseudomonas aeruginosa, a clinically challenging pathogen, it remains unclear whether the host can exploit this strategy to combat bacterial invasion. Here, we identify phosphoglycerate dehydrogenase as a key mediator of macrophage inflammation during Pseudomonas aeruginosa infection. Pharmacological and genetic inhibition of phosphoglycerate dehydrogenase suppress macrophage hyperactivation and the production of pro-inflammatory cytokines. In a murine model of Pseudomonas aeruginosa pneumonia, myeloid-specific deletion of phosphoglycerate dehydrogenase improves survival, alleviates lung injury, and reduces bacterial load. Similarly, dietary restriction of L-serine improves prognosis in infected mice. Mechanistically, phosphoglycerate dehydrogenase fuels L-serine synthesis to augment one-carbon metabolism, which strengthens the direct interaction between histone H3 lysine 27 trimethylation and dual-specificity phosphatase 4. This cascade ultimately promotes extracellular signal-regulated kinase 1/2 phosphorylation. Our study uncovers a metabolism-epigenetics crosstalk that amplifies macrophage inflammation, proposing metabolic modulation as a therapeutic strategy for bacterial pneumonia.