Redox-sensitive activation of CCL7 by BRG1 in hepatocytes during liver injury.
Redox-sensitive activation of CCL7 by BRG1 in hepatocytes during liver injury.
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DOI：
10.1016/j.redox.2021.102079
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发表时间：
2021-10
期刊：
影响因子：
11.4
通讯作者：
Xu Y
中科院分区：
文献类型：
--
作者：
Kong M;Dong W;Zhu Y;Fan Z;Miao X;Guo Y;Li C;Duan Y;Lu Y;Li Z;Xu Y
由各种刺激诱导的肝损伤共有急性炎症反应，其中循环巨噬细胞归巢至肝实质以参与修复、再生和纤维化的调节。在本研究中，我们研究了肝细胞衍生的C-C基序配体7（CCL 7）在肝损伤过程中巨噬细胞迁移中的作用，重点是其转录调控。我们报告说，CCL 7的表达上调，在肝脏脂多糖（LPS）注射（急性肝损伤）或蛋氨酸和胆碱缺乏（MCD）饮食喂养（慢性肝损伤）平行增加巨噬细胞浸润。CCL 7的表达也诱导肝细胞，但不是在肝星状细胞或枯否细胞，通过LPS处理或暴露于棕榈酸酯在体外。Brahma相关基因1（BRG 1），一种染色质重塑蛋白的肝细胞特异性缺失导致小鼠肝脏中CCL 7诱导和巨噬细胞浸润的伴随损失。有趣的是，BRG 1诱导的CCL 7转录和巨噬细胞迁移被抗氧化剂N-乙酰胱氨酸完全阻断。进一步的分析表明，BRG 1与激活蛋白1（AP-1）相互作用，以氧化还原敏感的方式调节肝细胞中的CCL 7转录，部分介导的酪蛋白激酶2（CK 2）催化的BRG 1磷酸化。重要的是，在人肝活检标本中鉴定了BRG 1/CCL 7表达与巨噬细胞浸润之间的正相关性。总之，我们的数据揭示了BRG 1作为CCL 7转录的氧化还原敏感性激活剂的新作用。
Liver injuries induced by various stimuli share in common an acute inflammatory response, in which circulating macrophages home to the liver parenchyma to participate in the regulation of repair, regeneration, and fibrosis. In the present study we investigated the role of hepatocyte-derived C–C motif ligand 7 (CCL7) in macrophage migration during liver injury focusing on its transcriptional regulation. We report that CCL7 expression was up-regulated in the liver by lipopolysaccharide (LPS) injection (acute liver injury) or methionine-and-choline-deficient (MCD) diet feeding (chronic liver injury) paralleling increased macrophage infiltration. CCL7 expression was also inducible in hepatocytes, but not in hepatic stellate cells or in Kupffer cells, by LPS treatment or exposure to palmitate in vitro. Hepatocyte-specific deletion of Brahma-related gene 1 (BRG1), a chromatin remodeling protein, resulted in a concomitant loss of CCL7 induction and macrophage infiltration in the murine livers. Of interest, BRG1-induced CCL7 transcription and macrophage migration was completely blocked by the antioxidant N-acetylcystine. Further analyses revealed that BRG1 interacted with activator protein 1 (AP-1) to regulate CCL7 transcription in hepatocytes in a redox-sensitive manner mediated in part by casein kinase 2 (CK2)-catalyzed phosphorylation of BRG1. Importantly, a positive correlation between BRG1/CCL7 expression and macrophage infiltration was identified in human liver biopsy specimens. In conclusion, our data unveil a novel role for BRG1 as a redox-sensitive activator of CCL7 transcription.
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