TREM2 improves coagulopathy and lung inflammation in sepsis through the AKT-mTOR pathway.

BACKGROUND

Sepsis is a systemic inflammatory response syndrome triggered by infection, often accompanied by severe coagulopathy, leading to high mortality. Tissue factor (TF) plays a pivotal role in sepsis by promoting both coagulation and inflammation. Recently, TREM2 (Triggering Receptor Expressed on Myeloid cells 2) has emerged as a key regulator of macrophage function, but its specific role in sepsis remains unclear.

METHODS

An in vitro sepsis model was established by stimulating RAW264.7 cells with 10 μg/mL lipopolysaccharide (LPS) for 6 h, with four groups: Negative Control (NC), NC + LPS, TREM2, and TREM2 + LPS. Inflammatory cytokines and coagulation factors were measured in each group. Cells in the TREM2 and TREM2 + LPS groups were pretreated with TREM2 overexpression plasmid for 48 h. In vivo, mice were assigned to Sham, TREM2, Cecal Ligation and Puncture (CLP), CLP + NC, and CLP + TREM2 groups. Mice in the NC group received macrophages via tail vein injection, while those in the TREM2 and CLP + TREM2 groups received TREM2-overexpressing macrophages. Lung tissue and plasma samples were collected to assess inflammatory cytokines, coagulation factors, and signaling pathway activity.

RESULTS

TREM2 overexpression significantly improved survival, reduced lung inflammation, and alleviated coagulopathy in mice. It increased platelet counts and reduced fibrin deposition. Furthermore, TREM2 inhibited TF release from macrophages by suppressing aberrant activation of the AKT-mTOR signaling pathway, thereby modulating the macrophage inflammatory response.

CONCLUSIONS

TREM2 plays a crucial protective role in sepsis-associated coagulopathy, suggesting that it could serve as a potential therapeutic target, providing novel strategies to improve clinical outcomes in sepsis patients.