Guanine promotes acute lung injury by repressing H3K27me3 in sepsis

Sepsis is systemic inflammation with high mortality, accompanied by multi-organ failure including acute respiratory distress syndrome. Extracellular vesicles (EVs) encapsulating bioactive cargoes, mediate cell-cell communication to exert systemic regulation. However, whether and how host lung tissue responds quickly to plasma bacterial infection through EVs in sepsis is poorly understood. Here, we identify that peripheral blood macrophages secrete more exosomal G6PD protein to induce lung injury by rewiring purine metabolism during sepsis. Guanine accumulation reduces H3K27 trimethylation and subsequently induces Nos2, Ccl6 and Il6 expression by suppressing de novo EZH2 synthesis. Macrophage-specific Rab27a or G6pd knockout mice had low exosomal G6PD protein in serum, and failed to exert lung injury upon bacterial infection. Beyond, targeting macrophage-derived G6PD by G6PD inhibitors or engineered EVs delivering si-G6pd relieves lung injury in septic mice. In summary, our findings reveal that circulating G6PD promotes lung injury by rewiring purine metabolism and remodeling the epigenetic profile in sepsis, shedding light on the critical role of EVs as a pro-inflammatory signal and targeting G6PD for future sepsis diagnosis and treatment.