Bone Marrow Mesenchymal Stem Cell-derived Exosomes Attenuate Sepsis-induced ARDS Through Inhibiting HIF-1α-mediated Glycolysis In Macrophage

Macrophages play a key role in the development of sepsis-induced acute respiratory distress syndrome(ARDS).Recent evidence has proved that glycolysis plays an important role in regulating macrophage polarization through metabolic reprogramming.Bone marrow mesenchymal stem cells(BMSCs)can alleviate sepsis-induced lung injury and possess potent immunomodulatory and immunosuppressive properties via secreting exosomes.However,it is unknown whether BMSCs-derived exosomes exert their therapeutic effect against sepsis-induced lung injury by inhibiting glycolysis in macrophages.Therefore,the present study aimed to evaluate the anti-inflammatory effects of exosomes released from BMSCs on acute lung injury induced by sepsis in mice and explored the possible underlying mechanisms in vitro and in vivo.We found that BMSCs inhibited M1 polarization and promoted M2 polarization in MH-S cells(a murine alveolar macrophage cell line)by releasing exosomes.Further experiments showed that exosomes secreted by BMSCs modulated LPS-treated MH-S cells polarization by inhibiting cellular glycolysis.Moreover,our results showed that BMSCs-derived exosomes down-regulated the expression of several essential proteins of glycolysis via inhibition of HIF-1α.Finally,a model of sepsis-induced ARDS in mice was established,we found that BMSCs-derived exosomes ameliorated the LPS-induced inflammation and lung pathological damage.Meanwhile,we found that intratracheal delivery of BMSCs-derived exosomes effectively down-regulated sepsis-induced glycolysis in mice lung tissue.These findings reveal new mechanisms of BMSCs-derived exosomes in regulating macrophage polarization which may provide novel strategies for the prevention and treatment of sepsis-induced ARDS.