NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease.
NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease.
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DOI：
10.1038/srep46144
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发表时间：
2017-04-06
影响因子：
4.6
通讯作者：
Török NJ
中科院分区：
文献类型：
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作者：
Sasaki Y;Dehnad A;Fish S;Sato A;Jiang J;Tian J;Schröder K;Brandes R;Török NJ
然而，炎症细胞的募集是酒精性肝损伤的一个主要特征；调控这一过程的信号和细胞源还没有很好地定义。C-C趋化因子受体2型（CCR2）由活跃的肝星状细胞（HSC）表达，是一个关键的单核细胞募集信号。活化的HSC也是NADPH氧化酶4 （NOX4）活化产生的过氧化氢的重要来源。由于NOX在早期酒精性肝损伤中的作用尚未得到解决，我们研究了nox4介导的CCR2/CCL2 mRNA稳定性的调节。NOX4 mRNA在酒精性肝损伤患者中被显著诱导，并与表达α sma的活化HSC共定位。我们制造了hsc特异性NOX4 KO小鼠，并将这些小鼠配对喂食酒精饮食。脂质过氧化无明显变化，但与fl/fl小鼠相比，NOX4HSCKO中CCR2、CCL2、Ly6C、TNFα和IL-6的表达显著降低。在乙醛处理的HSC中诱导NOX4启动子，NOX4显著增加CCR2和CCL2 mRNA的半衰期，并与Ser221磷酸化和HuR的细胞质穿梭有关。综上所述，NOX4在早期酒精性肝损伤中被诱导，调节CCR2/CCL2 mRNA的稳定性，从而促进炎症细胞的募集和促炎细胞因子的产生。
Recruitment of inflammatory cells is a major feature of alcoholic liver injury however; the signals and cellular sources regulating this are not well defined. C-C chemokine receptor type 2 (CCR2) is expressed by active hepatic stellate cells (HSC) and is a key monocyte recruitment signal. Activated HSC are also important sources of hydrogen peroxide resulting from the activation of NADPH oxidase 4 (NOX4). As the role of this NOX in early alcoholic liver injury has not been addressed, we studied NOX4-mediated regulation of CCR2/CCL2 mRNA stability. NOX4 mRNA was significantly induced in patients with alcoholic liver injury, and was co-localized with αSMA-expressing activated HSC. We generated HSC-specific NOX4 KO mice and these were pair-fed on alcohol diet. Lipid peroxidation have not changed significantly however, the expression of CCR2, CCL2, Ly6C, TNFα, and IL-6 was significantly reduced in NOX4HSCKO compared to fl/fl mice. NOX4 promoter was induced in HSC by acetaldehyde treatment, and NOX4 has significantly increased mRNA half-life of CCR2 and CCL2 in conjunction with Ser221 phosphorylation and cytoplasmic shuttling of HuR. In conclusion, NOX4 is induced in early alcoholic liver injury and regulates CCR2/CCL2 mRNA stability thereby promoting recruitment of inflammatory cells and production of proinflammatory cytokines.