AMSC-derived exosomes alleviate lipopolysaccharide/D-galactosamine-induced acute liver failure by miR-17-mediated reduction of TXNIP/NLRP3 inflammasome activation in macrophages

作者：Liu, Yanning; Lou, Guohua; Li, Aichun; Zhang, Tianbao; Qi, Jinjin; Ye, Dan; Zheng, Min^*; Chen, Zhi

来源：EBioMedicine, 2018, 36: 140-150.

DOI：10.1016/j.ebiom.2018.08.054

• Mesenchymal stem cells
• Exosome
• Macrophage
• miR-17
• TXNIP
• NLRP3 inflammasome

Background: Mesenchymal stem cell (MSC)-derived exosome administration has been considered as a novel cell-free therapy for liver diseases through cell-cell communication. This study was aimed to determine the effects and mechanisms of AMSC-derived exosomes (AMSC-Exo) for acute liver failure (ALF) treatment. @@@ Methods: AMSC-Exo were intravenously administrated into the mice immediately after lipopolysaccharide and D-galactosamine (LPS/GalN)-exposure and their effects were evaluated by liver histological and scrum biochemical analysis. To elucidate its mechanisms in ALF therapy, the expression levels of miRNAs and inflammasome-related genes in macrophages were evaluated by qPCR and Western blot analysis, respectively. The exosomes from miR-17-knockdowned AMSCs (AMSC-Exo(miR-1-KD)) were used for further determine the role of miR-17 in AMSC-Exo-based therapy. @@@ Findings: AMSC-Exo administration significantly ameliorated ALF as determined by reduced serum alanine aminotransferase and aspartate aminotransferase levels and hepatic inflammasome activation. Further experiments revealed that AMSC-Exo were colocalized with hepatic macrophages and could reduce inflammatory factor secretion by suppressing inflammasome activation in macrophages. Moreover, miR-17, which can suppress NLRP3 inflammasome activation by targeting TXNIP, was abundant in AMSC-Exo cargo. While, the therapeutic effects of AMSC-Exo(miR-1-KD) on ALF were significantly abolished as they could not effectively suppress TXNIP expression and consequent inflammasome activation in vitro and in vivo. @@@ Interpretation: Exosome-shuttled miR-17 plays an essential role in AMSC-Exo therapy for ALF by targeting TXNIP and suppressing inflammasome activation in hepatic macrophages. AMSC-Exo-based therapy may present as a promising approach for TXNIP/NLRP3 inflammasome-related inflammatory liver diseases.

• 出版日期2018-10
• 单位浙江大学