TREM2 sustains glucose metabolic homeostasis to drive antibacterial defense during sepsis.

Metabolic disturbances, particularly glucose imbalances, are common in sepsis and are strongly associated with increased mortality. However, the mechanisms underlying glucose dyshomeostasis remain poorly understood. Here, we revealed the role of triggering receptor expressed on myeloid cells 2 (TREM2) in regulating glucose metabolism during sepsis. Macrophage-specific TREM2 deficiency significantly increased the level of abdominal IL-1β, which is predominantly released by pyroptotic peritoneal macrophages. IL-1β then acts on IL-1R1 receptors on pancreatic islet β-cells, promoting insulin release and inducing hypoglycemia. Transfusing TREM2-overexpressing macrophages and administering glucose solutions can restore glucose homeostasis and improve sepsis outcomes in mice. In summary, our study reveals a mechanism by which TREM2 orchestrates glucose metabolism during sepsis and highlights the potential of TREM2 as a therapeutic target for sepsis.