Pharmacological elevation of lactate alleviates sepsis via histone lactylation-induced IL-10 production - PubMed
5 days ago
- #Sepsis
- #Lactate
- #Amlexanox
- Lactate accumulation is traditionally seen as a marker of severe sepsis, but it also induces histone lactylation, which promotes the transcription of homeostatic genes.
- Amlexanox, an anti-inflammatory drug, improves survival, reduces multiorgan dysfunction, and suppresses inflammatory responses in endotoxemia and sepsis.
- Amlexanox increases intracellular lactate levels, enhancing histone lactylation at the IL10 gene promoter, leading to increased IL-10 production, which alleviates sepsis.
- Blocking the IL-10 receptor nearly eliminates the therapeutic effects of amlexanox, and inhibiting lactate production stops amlexanox-induced IL-10 increase.
- Amlexanox disrupts the electron transport chain, reduces oxygen consumption rate (OCR), and increases extracellular acidification rate (ECAR), indicating a shift from aerobic respiration to lactate production.
- In vivo administration of sodium lactate improves survival in endotoxemia, supporting the protective role of lactate-mediated histone lactylation in sepsis.
- The study highlights amlexanox as a potential therapeutic drug for sepsis by leveraging lactate-mediated histone lactylation.