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

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. Metabolic reprogramming of immune cells can modulate their response to and ability to respond in infective contexts. Here the authors show phosphoglycerate dehydrogenase mediated serine reprogramming in macrophage is linked to hyper inflammatory responses in murine models of Pseudomonas aeruginosa pneumonia.