Pim1 induces M1 polarization of peritoneal macrophage and aggravates sepsis by upregulating glycolysis

Abstract Peritoneal macrophages play a crucial role in sepsis and the resulting organ damage. However, the precise mechanism through which peritoneal macrophages contribute to sepsis remains incompletely understood. The scRNA-seq and RNA-seq have revealed that the septic environment can enhance glycolysis and promote M1 polarization in peritoneal macrophages. Pim1 is a key player in this process. Inhibiting Pim1 expression effectively mitigates glycolysis in macrophages and reduces M1 polarization. As a transcription factor, C-Myc interacts with Pim1, regulating its protein expression and phosphorylation levels. Chromatin immunoprecipitation (ChIP) experiments have confirmed that C-Myc binds to the promoter region of crucial glycolytic genes, enhancing gene transcription and glycolysis. Administration of a Pim1 inhibitor in CLP mice can alleviate glycolysis and M1 polarization in peritoneal macrophages, thereby effectively reducing lung injury. We identified that sepsis-induced Pim1 promotes the transcription of glycolytic genes and M1 polarization in macrophages by modulating c-Myc phosphorylation levels, exacerbating sepsis-related lung injury. This study provided novel insights into M1 polarization of peritoneal macrophage during the infection and revealed potential molecular and metabolic targets for the regulation of sepsis.