PFKFB3-involved glycolytic metabolism supports sepsis-induced neutrophil extracellular trap formation

Uncontrolled formation of neutrophil extracellular traps (NETs) is one of the main mechanisms leading to death in septic patients. PFKFB3, a notable enzyme of glycolysis metabolism, is involved in the inflammatory activation of granulocytes. Our previous studies demonstrated that PFKFB3-involved glycolytic metabolism supports CXCR4^hi neutrophil inflammatory activation, which is a key mechanism for the inflammatory injury of the lungs induced by sepsis. However, the specific mechanism by which PFKFB3 supports NET formation in sepsis remains unclear. Here, we found that high expression of neutrophil PFKFB3 is essential for sepsis-induced NET formation. Further mechanistic studies revealed that PFKFB3 promoted sepsis-related NET formation via glycolytic reprogramming and peptidylarginine deiminase 4 (PAD4)-dependent chromatin decondensation. However, inhibiting glycolytic metabolism supported by PFKFB3 can significantly reduce PAD4-dependent NET formation and alleviate sepsis-related lung inflammatory damage. In summary, our results revealed that PFKFB3-supported glycolytic metabolism promotes sepsis-induced NET formation via PAD4-mediated chromatin decondensation. Targeting PFKFB3-supported glycolysis represents a potential strategy to alleviate sepsis-induced hyperinflammation and tissue damage.