Mitochondrial DNA-enriched microparticles promote acute-on-chronic alcoholic neutrophilia and hepatotoxicity
Mitochondrial DNA-enriched microparticles promote acute-on-chronic alcoholic neutrophilia and hepatotoxicity
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DOI：
10.1172/jci.insight.92634
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发表时间：
2017-07-20
期刊：
影响因子：
8
通讯作者：
Gao, Bin
中科院分区：
文献类型：
--
作者：
Cai, Yan;Xu, Ming-Jiang;Gao, Bin
在过去的几年里，酒精性肝病研究领域的一个主要进展是发现，在长期乙醇喂养的小鼠和过度饮酒的人类受试者（EAU）中，酗酒会诱导嗜中性粒细胞和肝脏中性粒细胞浸润;然而，潜在的机制仍然不清楚。在这里，我们证明了有近期过量饮酒史的慢性EAU患者（EAU + RD）的血清线粒体DNA（mtDNA）富集微粒（MP）水平高于近期无饮酒史的EAU（EAU-RD）和健康对照组，其与循环中性粒细胞呈正相关。类似地，慢性加狂欢（E10 d + 1B）乙醇喂养的小鼠也具有显著升高的血清mtDNA富集MP水平，并激活肝脏ER应激和炎症反应。通过基因KO或抑制剂抑制ER应激可减弱乙醇诱导的富含mtDNA的MP升高、嗜中性粒细胞增多和肝损伤。来自小鼠和培养的肝细胞中蛋白激酶RNA样ER激酶（Perk）基因的肝细胞特异性缺失的研究数据表明，肝细胞是乙醇喂养后富含mtDNA的MP的主要来源。最后，从E10 d +1B喂养的小鼠中分离的富含mtDNA的MP的给药引起小鼠的嗜中性粒细胞。总之，E10 d + 1B乙醇消耗激活肝脏ER应激依赖性mtDNA富集MP释放，导致嗜中性粒细胞和肝损伤。
Over the last several years, one of the major advances in the field of alcoholic liver disease research was the discovery that binge alcohol consumption induced neutrophilia and hepatic neutrophil infiltration in chronically ethanol-fed mice and human subjects with excessive alcohol use (EAU); however, the underlying mechanisms remain obscure. Here, we demonstrated that chronic EAU patients with a history of recent excessive drinking (EAU + RD) had higher serum levels of mitochondrial DNA (mtDNA)-enriched microparticles (MPs) than EAU without recent drinking (EAU -RD) and healthy controls, which correlated positively with circulating neutrophils. Similarly, mice with chronic-plus-binge (E10d + 1B) ethanol feeding also had markedly elevated serum levels of mtDNA-enriched MPs, with activation of hepatic ER stress and inflammatory responses. Inhibition of ER stress by gene KO or inhibitors attenuated ethanol-induced elevation of mtDNA-enriched MPs, neutrophilia, and liver injury. The data from the study of hepatocyte-specific deletion of the protein kinase RNA-like ER kinase (Perk) gene in mice and of cultured hepatocytes demonstrated that hepatocytes were the main source of mtDNA-enriched MPs after ethanol feeding. Finally, administration of mtDNA-enriched MPs isolated from E10d+ 1B-fed mice caused neutrophilia in mice. In conclusion, E10d + 1B ethanol consumption activates hepatic ER stress-dependent mtDNA-enriched MP release, leading to neutrophilia and liver injury.