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Alveolar Macrophage Phagocytosis and Bacteria Clearance in Mice
Published on: March 2, 2019
Phosphoglycerate dehydrogenase-mediated serine reprogramming aggravates macrophage hyperinflammation in murine
Rong Chen1,2,3, Ran Zeng1,2,3, Mengmeng Shi1,2,3
1Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
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.
Insights
Researchers found that inhibiting phosphoglycerate dehydrogenase reduces inflammation and improves survival in Pseudomonas aeruginosa pneumonia. This metabolic pathway fuels L-serine synthesis, offering a potential therapeutic target for bacterial infections.
Area of Science:
- Immunology
- Metabolic pathways
- Microbiology
Background:
- Metabolic reprogramming in immune cells influences infection outcomes.
- The role of host metabolic strategies against Pseudomonas aeruginosa is not well understood.
Purpose of the Study:
- To investigate the role of phosphoglycerate dehydrogenase in macrophage inflammation during Pseudomonas aeruginosa infection.
- To explore metabolic modulation as a therapeutic strategy for bacterial pneumonia.
Main Methods:
- Identified phosphoglycerate dehydrogenase as a key mediator.
- Utilized pharmacological and genetic inhibition of phosphoglycerate dehydrogenase.
- Employed a murine model of Pseudomonas aeruginosa pneumonia.
- Investigated the link between L-serine synthesis, one-carbon metabolism, and epigenetic modifications.
Main Results:
- Inhibition of phosphoglycerate dehydrogenase suppressed macrophage hyperactivation and pro-inflammatory cytokine production.
- Myeloid-specific deletion of phosphoglycerate dehydrogenase improved survival, reduced lung injury, and decreased bacterial load in mice.
- Dietary restriction of L-serine improved prognosis in infected mice.
- Discovered a mechanism involving phosphoglycerate dehydrogenase, L-serine synthesis, one-carbon metabolism, histone modifications, and ERK1/2 phosphorylation.
Conclusions:
- Phosphoglycerate dehydrogenase is a critical mediator of macrophage inflammation in Pseudomonas aeruginosa infection.
- Metabolic reprogramming, specifically L-serine synthesis, amplifies inflammation through a metabolism-epigenetics crosstalk.
- Targeting phosphoglycerate dehydrogenase and related metabolic pathways presents a promising therapeutic strategy for bacterial pneumonia.
