Sphingosine 1-phosphate/microRNA-1249-5p/MCP-1 axis is involved in macrophage-associated inflammation in fatty liver injury in mice
Sphingosine 1-phosphate/microRNA-1249-5p/MCP-1 axis is involved in macrophage-associated inflammation in fatty liver injury in mice
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DOI：
10.1002/eji.201948351
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发表时间：
2020-08-13
影响因子：
5.4
通讯作者：
Li, Liying
中科院分区：
文献类型：
--
作者：
Ji, Xiaofang;Yang, Le;Li, Liying
单核细胞趋化蛋白-1（MCP-1）是最具代表性的炎性细胞因子之一，已被证明在肝损伤和1-磷酸鞘氨醇（S1 P）处理的巨噬细胞中显著升高。然而，靶向MCP-1的microRNAs（miRNAs）和miRNA/MCP-1轴在S1 P介导的肝脏炎症中的作用在很大程度上仍然未知。在这里，我们证明，MCP-1的表达增加，在肝脏和分离的肝脏巨噬细胞MCDHF小鼠。此外，肝脏S1 P和MCP-1水平之间存在正相关性。然后通过生物信息学分析预测靶向MCP-1的miRNAs，并从TargetScan数据库和损伤肝脏中下调的miRNAs的交叉点中筛选miRNAs-1249- 5 p（miR-1249- 5 p）。S1 P显著上调巨噬细胞中MCP-1的表达并降低miR-1249- 5 p的表达。miR-1249- 5 p直接靶向MCP-1的3 '-UTR，并在S1 P处理的巨噬细胞中负调控其表达。miR-1249- 5 p agomir可降低MCDHF小鼠肝脏MCP-1水平并减轻肝脏炎症。STRING蛋白质相互作用网络显示S1 P系统与炎症网络中的MCP-1/CCR 2轴密切相关。总之，我们表征了miR-1249- 5 p在体外和体内负调控MCP-1表达中的重要作用，这可能为肝脏疾病的药物治疗开辟新的前景。
Monocyte chemotactic protein-1 (MCP-1) is one of the most representative inflammatory cytokines, and has been proved to be markedly increased in injured liver and sphingosine 1-phosphate (S1P)-treated macrophages. However, microRNAs (miRNAs) targeting MCP-1 and the role of miRNA/MCP-1 axis in S1P-mediated liver inflammation remain largely unknown. Here, we demonstrate that MCP-1 expression is increased in the liver and isolated liver macrophages of MCDHF mice. Moreover, there is a positive correlation between the hepatic levels of S1P and MCP-1. We then predict miRNAs targeting MCP-1 by bioinformatics analysis and select miRNA-1249-5p (miR-1249-5p) from the intersection of TargetScan database and downregulated miRNAs in the injured liver. S1P significantly upregulates the expression of MCP-1 and decreases miR-1249-5p expression in macrophages. MiR-1249-5p directly targets 3'-UTR of MCP-1 and negatively regulates its expression in S1P-treated macrophages. Administration of miR-1249-5p agomir decreases hepatic MCP-1 levels and attenuates liver inflammation in MCDHF mice. Protein-protein interaction network by STRING displays that S1P system is closely associated with MCP-1/CCR2 axis in the network of inflammation. In conclusion, we characterize the vital role of miR-1249-5p in negatively regulating MCP-1 expression in vitro and in vivo, which may open new perspectives for pharmacological treatment of liver disease.