Bone marrow mesenchymal stem cell-derived exosomes alleviating sepsis-induced lung injury by inhibiting ferroptosis of macrophages

Abstract

Objective: To investigate whether bone marrow mesenchymal stem cells derived exosomes (BMSCs-exo) can alleviate sepsis-induced lung injury and its related mechanism by inhibiting ferroptosis of macrophages.

Methods: RAW264.7 cells were first stimulated with lipopolysaccharide (LPS) to observe whether macrophage ferroptosis occurred. After pre-treating BMSCs with the exosome inhibitor GW4869, the lung-protective effect was observed to determine if it was eliminated. Furthermore, BMSCs-exo was extracted to clarify if it could exert effects like BMSCs. Finally, key molecules responsible for the effects were identified through sequencing and other related techniques.

Results: Following stimulation with LPS, the expression of GPX4 in RAW264.7 cells decreased significantly, while the expression of PTGS2 increased significantly. The intracellular GSH content decreased, while MDA content increased. BMSCs-exo reversed the decrease in GPX4 and increase in PTGS2, increased GSH and decreased MDA. Sequencing revealed that lncRNA SNHG12 in macrophages was significantly upregulated after co-culture with BMSCs-exo. Knockdown of lncRNA SNHG12 in BMSCs via siRNA resulted in a significant decrease in the inhibitory effect on macrophage ferroptosis both in vivo and in vitro.

Conclusion: BMSCs-exo can inhibit macrophage ferroptosis through lncRNA SNHG12, thereby alleviating the sepsis-induced lung injury and improving the survival rate.

Keywords: Acute respiratory distress syndrome; Bone marrow mesenchymal stem cells; Exosome; Ferroptosis; Macrophages.