Sepsis induces non-classic innate immune memory in granulocytes.

Secondary infection in patients with sepsis triggers a new wave of inflammatory response, which aggravates organ injury and increases mortality. Trained immunity boosts a potent and nonspecific response to the secondary challenge and has been considered beneficial for the host. Here, using a murine model of polymicrobial infection, we find that the primary infection reprograms granulocytes to boost enhanced inflammatory responses to the secondary infection, including the excessive production of inflammatory cytokines, respiratory burst, and augmented phagocytosis capacity. However, these reprogramed granulocytes exhibit "non-classic" characteristics of innate immune memory. Two mechanisms are independently involved in the innate immune memory of granulocytes: a metabolic shift in favor of glycolysis and fatty acid synthesis and chromatin remodeling leading to the transcriptional inactivity of genes encoding inhibitors of TLR4-initiated signaling pathways. Counteracting the deleterious effects of stressed granulocytes on anti-infection immunity might provide a strategy to fight secondary infections during sepsis. [Display omitted] • Sepsis induces innate immune memory in stressed granulocytes • Stressed granulocytes boost fatal inflammatory responses to secondary infections • Chromatin remodeling of the TLR4 pathway and metabolic shift work independently • Stressed granulocytes specifically target lungs by the CXCL2-CXCR2 axis In septic mice, Wang et al. identify stressed granulocytes with innate immune memory. These stressed granulocytes pose an amplified immune response, specifically causing lung injuries and increasing mortality during secondary infections. The study explains how stressed granulocytes determine host fate in secondary infections after sepsis. [ABSTRACT FROM AUTHOR]