ATG2B upregulated in LPS-stimulated BMSCs-derived exosomes attenuates septic liver injury by inhibiting macrophage STING signaling.

Abstract

Pretreated mesenchymal stem cells (MSCs)-derived exosomes have shown great potential in the treatment of various inflammatory diseases. Recent evidence suggests that macrophage stimulator of interferon genes (STING) signal activation plays a critical role in sepsis and septic liver injury. Here, we aimed to investigate the role and effects of lipopolysaccharide (LPS)-pretreated bone marrow mesenchymal stem cells (BMSCs)-derived exosomes (L-Exo) on macrophage STING signaling in septic liver injury. Exosomes were collected from the BMSCs medium via ultracentrifugation. Liver injury, intrahepatic inflammation, and the activation of macrophage STING signaling were analyzed. Mitophagy and the release of mitochondrial DNA (mtDNA) into the cytosol were investigated. Through in vivo and in vitro experiments, L-Exo could markedly attenuate cecal ligation and puncture-induced septic liver injury and inhibit macrophage STING signaling. Mechanistically, L-Exo inhibited macrophage STING signaling by enhancing mitophagy and inhibiting the release of mtDNA into the cytosol. Furthermore, autophagy-related protein 2 homolog B (ATG2B) may be a major factor involved in this effect of L-Exo. These findings reveal that macrophage STING signaling plays an important role in septic liver injury and may be a therapeutic target. In addition, LPS pretreatment is an effective and promising approach for optimizing the therapeutic efficacy of MSCs-derived exosomes in septic liver injury, providing new strategies for treatment.