Comprehensive characterization of hepatocyte-derived extracellular vesicles identifies direct miRNA-based regulation of hepatic stellate cells and DAMP-based hepatic macrophage IL-1β and IL-17 upregulation in alcoholic hepatitis mice.
Comprehensive characterization of hepatocyte-derived extracellular vesicles identifies direct miRNA-based regulation of hepatic stellate cells and DAMP-based hepatic macrophage IL-1β and IL-17 upregulation in alcoholic hepatitis mice.
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DOI：
10.1007/s00109-020-01926-7
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发表时间：
2020-07
期刊：
影响因子：
--
通讯作者：
Tsukamoto H
中科院分区：
文献类型：
--
作者：
Eguchi A;Yan R;Pan SQ;Wu R;Kim J;Chen Y;Ansong C;Smith RD;Tempaku M;Ohno-Machado L;Takei Y;Feldstein AE;Tsukamoto H
细胞外囊泡（EVs）是人类和小鼠酒精性肝病（ALD）的生物标志物和介质。在这里，我们在一种新型小鼠模型中对肝细胞衍生的EV（HC-EV）及其货物的生物学功能进行了表征，该模型与酒精性肝炎（AH）患者（最严重的酒精性肝炎）中观察到的肝脏病理学非常相似。与对照小鼠相比，AH小鼠中循环EV和HC-EV的数量显著增加了10倍。miRNA（miR）-seq分析在AH-HC-EV中检测到20种上调和4种下调的miRNA（P < 0.001-0.05）。AH-HC-EV处理小鼠原代肝星状细胞（HSC）可诱导α-SMA（P < 0.05）和Col 1a 1（P < 0.001）。Smad 7和Nr 1d 2基因在来自AH小鼠的HSC中下调，是AH-HC-EV中上调的20个miR的预测靶点。其中包括miR-27 a和miR-181，它们在HSC中转染后，确实抑制了静止HSC标记物Nr 1d 2。AH-HC-EV还富含细胞器蛋白和线粒体DNA（10倍，P < 0.05），并且以TLR 9依赖性方式上调来自AH小鼠的肝巨噬细胞（HM）产生IL-1β和IL-17。这些结果表明，HC-EV释放在AH中增强，并表明AH-HC-EV通过经由一组独特的miRNA直接靶向静止HSC转录物以及通过由HM经由基于DAMP的促纤维化IL-1β和IL-17的诱导来放大HSC活化来协调肝纤维化。
Extracellular vesicles (EVs) have been growingly recognized as biomarkers and mediators of alcoholic liver disease (ALD) in human and mice. Here we characterized hepatocyte-derived EVs (HC-EVs) and their cargo for their biological functions in a novel murine model that closely resembles liver pathology observed in patients with alcoholic hepatitis (AH), the most severe spectrum of ALD. The numbers of circulating EVs and HC-EVs were significantly increased by 10-fold in AH mice compared with control mice. The miRNA (miR)–seq analysis detected 20 upregulated and 4 downregulated miRNAs (P < 0.001–0.05) in AH-HC-EVs. Treatment of murine primary hepatic stellate cells (HSCs) with AH-HC-EVs induced α-SMA (P < 0.05) and Col1a1 (P < 0.001). Smad7 and Nr1d2 genes, which were downregulated in HSCs from the AH mice, were predicted targets of 20 miRs upregulated in AH-HC-EVs. Among them were miR-27a and miR-181 which upon transfection in HSCs, indeed repressed Nr1d2, the quiescent HSC marker. AH-HC-EVs were also enriched with organelle proteins and mitochondrial DNA (10-fold, P < 0.05) and upregulated IL-1β and IL-17 production by hepatic macrophages (HMs) from AH mice in a TLR9-dependent manner. These results demonstrate HC-EV release is intensified in AH and suggest that AH-HC-EVs orchestrate liver fibrogenesis by directly targeting the quiescent HSC transcripts via a unique set of miRNAs and by amplifying HSC activation via DAMP-based induction of profibrogenic IL-1β and IL-17 by HMs.
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DOI：
10.1016/j.jcmgh.2015.07.007
发表时间：
2015-11-01
影响因子：
7.2
作者：
Povero D;Panera N;Eguchi A;Johnson CD;Papouchado BG;de Araujo Horcel L;Pinatel EM;Alisi A;Nobili V;Feldstein AE
通讯作者：
Feldstein AE
DOI：
10.1093/bioinformatics/btu377
发表时间：
2014-10
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Kim J;Levy E;Ferbrache A;Stepanowsky P;Farcas C;Wang S;Brunner S;Bath T;Wu Y;Ohno-Machado L
通讯作者：
Ohno-Machado L
影响因子：
29.4
作者：
Meng F;Wang K;Aoyama T;Grivennikov SI;Paik Y;Scholten D;Cong M;Iwaisako K;Liu X;Zhang M;Österreicher CH;Stickel F;Ley K;Brenner DA;Kisseleva T
通讯作者：
Kisseleva T
影响因子：
15.9
作者：
Garcia-Martinez, Irma;Santoro, Nicola;Mehal, Wajahat Zafar
通讯作者：
Mehal, Wajahat Zafar
对乙酰氨基酚过量且预后不良的患者的血清线粒体生物标志物和损伤相关分子模式较高。
影响因子：
13.5
作者：
McGill, Mitchell R.;Staggs, Vincent S.;Sharpe, Matthew R.;Lee, William M.;Jaeschke, Hartmut
通讯作者：
Jaeschke, Hartmut