Maintenance of glutamine synthetase expression alleviates endotoxin-induced sepsis via alpha-ketoglutarate-mediated demethylation

Glutamine synthetase (Glul) is the enzyme that synthesizes endogenous glutamine, which is responsible for critical metabolic pathways and the immune system. However, the role of Glul in regulating endotoxin (lipopolysaccharide, LPS)-induced sepsis remains unclear. Here, we found that Glul expression in macrophages was significantly inhibited in endotoxemia, and that Glul deletion induced macrophages to differentiate into the pro-inflammatory type and aggravated sepsis in mice. Mechanistically, TLR4/NF-κB-induced alpha-ketoglutarate (α-KG) depletion inhibits Glul expression through H3K27me3-mediated methylation in septic mice. Both Glul overexpression with adeno-associated virus (AAV) and restoration by replenishing α-KG can alleviate the severity of sepsis. In conclusion, the study demonstrated that Glul can regulate LPS-induced sepsis and provides a novel strategy for the treatment of this disease.