A schistosome miRNA promotes host hepatic fibrosis by targeting transforming growth factor beta receptor III
A schistosome miRNA promotes host hepatic fibrosis by targeting transforming growth factor beta receptor III
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血吸虫 miRNA 通过靶向转化生长因子 β 受体 III 促进宿主肝纤维化
DOI：
10.1016/j.jhep.2019.10.029
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发表时间：
2020-03-01
影响因子：
25.7
通讯作者：
Pan, Weiqing
中科院分区：
文献类型：
--
作者：
He, Xing;Wang, Yange;Pan, Weiqing
背景与目的：来自寄生虫，甚至来自植物的MicroRNAs （MiRNAs）已经在体液中被检测到，并且已知可以调节宿主基因。在这项研究中，我们旨在探讨血吸虫mirna是否参与日本血吸虫感染期间肝纤维化的发生和进展。方法：采用RNA测序法检测日本血吸虫miRNAs （sja-miRNAs）在肝星状细胞（hsc）中的表达。用sja-miRNA模拟物转染hsc筛选sja-miRNA。通过分别给予表达sja-miR-2162或miRNA海绵的重组腺相关病毒血清8型载体，通过提高其在幼年小鼠中的表达或抑制其在感染小鼠中的活性来评估sja-miR-2162在肝纤维化中的作用。结果：我们鉴定了日本血吸虫的miRNA sja-miR-2162，该miRNA在感染小鼠的造血干细胞中一致存在。转染sja-miR-2162模拟物可在体外激活HSC细胞，其特征是胶原和α - sma的升高。raav8介导的sja-miR-2162传递给幼稚小鼠诱导肝纤维化，而在感染小鼠中持续抑制sja-miR-2162可减轻肝纤维化。转化生长因子β受体III （TGFBR3）是tgf - β信号的负调节因子，是hsc中sja-miR-2162的直接靶点。结论：本研究表明，病原体来源的mirna以跨物种的方式直接促进肝纤维化，其有效和持续的抑制可能为传染病的治疗干预提供了前景。概要：血吸虫特异性microRNA sja-miR-2162持续存在于日本血吸虫感染小鼠的肝星状细胞中，它通过跨物种调控宿主纤维化相关基因促进宿主肝纤维化。有效和持续抑制病原体来源的micRNAs可能代表一种新的治疗传染病的干预措施。(C) 2019欧洲肝脏研究协会。Elsevier B.V.版权所有。
Background & Aims: MicroRNAs (MiRNAs) derived from parasites, and even from plants, have been detected in body fluids and are known to modulate host genes. In this study, we aimed to investigate if the schistosome miRNAs are involved in the occurrence and progression of hepatic fibrosis during Schistosoma japonicum (S. japonicum) infection.Methods: The presence of miRNAs from S. japonicum (sja-miRNAs) in hepatic stellate cells (HSCs) was detected by RNA sequencing. sja-miRNAs were screened by transfecting HSCs with sja-miRNA mimics. The role of sja-miR-2162 in hepatic fibrosis was evaluated by either elevating its expression in naive mice or by inhibiting its activity in infected mice, through administration of recombinant adeno-associated virus serotype 8 vectors expressing sja-miR-2162 or miRNA sponges, respectively.Results: We identified a miRNA of S.japonicum, sja-miR-2162, that was consistently present in the HSCs of infected mice. Transfection of sja-miR-2162 mimics led to activation of HSC cells in vitro, characterized by elevation of collagens and alpha-SMA. The rAAV8-mediated delivery of sja-miR-2162 to naive mice induced hepatic fibrosis, while sustained inhibition of sja-miR-2162 in infected mice attenuated hepatic fibrosis. The transforming growth factor beta receptor III (TGFBR3), a negative regulator of TGF-beta signaling, was a direct target of sja-miR-2162 in HSCs.Conclusions: This study demonstrated that pathogen-derived miRNAs directly promote hepatic fibrogenesis in a cross-species manner, and their efficient and sustained inhibition might present a promising therapeutic intervention for infectious diseases.Lay summary: A schistosome-specific microRNA, sja-miR-2162, is consistently present in the hepatic stellate cells of mice infected with S. japonicum, where it promotes hepatic fibrosis in the host through cross-species regulation of host fibrosis-related genes. The efficient and sustained inhibition of pathogen-derived micRNAs may represent a novel therapeutic intervention for infectious diseases. (C) 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.