Neutrophil-to-hepatocyte communication via LDLR-dependent miR-223-enriched extracellular vesicle transfer ameliorates nonalcoholic steatohepatitis
Neutrophil-to-hepatocyte communication via LDLR-dependent miR-223-enriched extracellular vesicle transfer ameliorates nonalcoholic steatohepatitis
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DOI：
10.1172/jci141513
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发表时间：
2021-02-01
影响因子：
15.9
通讯作者：
Gao, Bin
中科院分区：
文献类型：
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作者：
He, Yong;Rodrigues, Robim M.;Gao, Bin
中性粒细胞在脂毒性肝细胞周围的渗透是非酒精性脂肪性肝炎(NASH)的一个标志；然而，这两种类型的细胞如何沟通仍不清楚。我们先前已经证明，中性粒细胞特异性microRNA-223(miR-223)在肝细胞中升高，以限制肥胖小鼠的NASH进展。在这里，我们证明，肝细胞中miR-223的升高是由于从中性粒细胞和其他类型的细胞中优先摄取富含miR-223的细胞外小泡(EV)，尽管程度较小。这种选择性摄取依赖于肝细胞上低密度脂蛋白受体(LDLR)和中性粒细胞来源的EV上的载脂蛋白E(APOE)的表达，而游离脂肪酸可以增强APOE的表达。一旦被肝细胞内化，EV来源的miR-223就能抑制肝脏炎症和纤维化基因的表达。在缺乏这种依赖LDLR和APOE的摄取miR-223富含EV的情况下，脂肪变性向NASH的进展加速。相反，通过抑制原蛋白转换酶枯草杆菌/可信9型来增强这种转移，一种用于通过上调低密度脂蛋白受体来降低血液胆固醇的药物，改善了小鼠的NASH。LDLR和APOE在选择性控制中性粒细胞向肝细胞转移miR-223丰富的EV中的这种特殊作用可能成为NASH潜在的治疗靶点。
Neutrophil infiltration around lipotoxic hepatocytes is a hallmark of nonalcoholic steatohepatitis (NASH); however, how these 2 types of cells communicate remains obscure. We have previously demonstrated that neutrophil-specific microRNA-223 (miR-223) is elevated in hepatocytes to limit NASH progression in obese mice. Here, we demonstrated that this elevation of miR-223 in hepatocytes was due to preferential uptake of miR-223-enriched extracellular vesicles (EVs) derived from neutrophils as well other types of cells, albeit to a lesser extent. This selective uptake was dependent on the expression of low-density lipoprotein receptor (LDLR) on hepatocytes and apolipoprotein E (APOE) on neutrophil-derived EVs, which was enhanced by free fatty acids. Once internalized by hepatocytes, the EV-derived miR-223 acted to inhibit hepatic inflammatory and fibrogenic gene expression. In the absence of this LDLR- and APOE-dependent uptake of miR-223-enriched EVs, the progression of steatosis to NASH was accelerated. In contrast, augmentation of this transfer by treatment with an inhibitor of proprotein convertase subtilisin/kexin type 9, a drug used to lower blood cholesterol by upregulating LDLR, ameliorated NASH in mice. This specific role of LDLR and APOE in the selective control of miR-223-enriched EV transfer from neutrophils to hepatocytes may serve as a potential therapeutic target for NASH.