当前位置: X-MOL 学术Front. Cell Dev. Biol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
BRG1 Mediates Nephronectin Activation in Hepatocytes to Promote T Lymphocyte Infiltration in ConA-Induced Hepatitis
Frontiers in Cell and Developmental Biology ( IF 5.5 ) Pub Date : 2020-12-10 , DOI: 10.3389/fcell.2020.587502
Wenxuan Hong , Ming Kong , Mengwen Qi , Hui Bai , Zhiwen Fan , Ziyu Zhang , Aijun Sun , Xiangshan Fan , Yong Xu

Fulminant hepatitis (FH) is a major cause of acute liver failure. Concanavalin A (ConA) belongs to the lectin family and is frequently used as an inducer of FH in animal models. ConA induced FH is characterized by massive accumulation of T lymphocytes in the liver. A host of chemoattractive substances are known to promote T cell homing to the liver during acute hepatitis. Here we investigated the involvement of Brahma-related gene 1 (BRG1), a chromatin remodeling protein, in FH. BRG1-flox mice were crossed to Alb-Cre mice to generate hepatocyte conditional BRG1 knockout (LKO) mice. The mice were peritoneally injected with a single dose of ConA to induce FH. BRG1 deficiency mitigated ConA-induced FH in mice. Consistently, there were fewer T lymphocyte infiltrates in the LKO livers compared to the wild type (WT) livers paralleling downregulation of T cell specific cytokines. Further analysis revealed that BRG1 deficiency repressed the expression of several chemokines critical for T cell homing including nephronectin (Npnt). BRG1 knockdown blocked the induction of Npnt in hepatocytes and attenuated T lymphocyte migration in vitro, which was reversed by the addition of recombinant nephronectin. Mechanistically, BRG1 interacted with β-catenin to directly bind to the Npnt promoter and activate Npnt transcription. Importantly, a positive correlation between infiltration of CD3+ T lymphocyes and nephronectin expression was detected in human acute hepatitis biopsy specimens. In conclusion, our data identify a novel role for BRG1 as a promoter of T lymphocyte trafficking by activating Npnt transcription in hepatocytes. Targeting the BRG1-Npnt axis may yield novel therapeutic solutions for FH.



中文翻译:

BRG1介导肾细胞内肾上腺素激活,以促进ConA诱导的肝炎中T淋巴细胞浸润。

暴发性肝炎(FH)是急性肝衰竭的主要原因。伴刀豆球蛋白A(ConA)属于凝集素家族,经常在动物模型中用作促性腺激素的诱导剂。ConA诱导的FH的特征是肝脏中T淋巴细胞大量积累。已知许多化学吸引性物质可在急性肝炎期间促进T细胞归巢至肝脏。在这里,我们调查了婆罗门相关基因1(BRG1),染色质重塑蛋白,在FH中的参与。将BRG1-flox小鼠与Alb-Cre小鼠杂交,以产生肝细胞条件性BRG1敲除(LKO)小鼠。给小鼠腹膜注射单剂量的ConA以诱导FH。BRG1缺乏症减轻了ConA诱导的小鼠FH。一致地,与下调T细胞特异性细胞因子的野生型(WT)肝脏相比,LKO肝脏中的T淋巴细胞浸润较少。进一步的分析表明,BRG1缺乏抑制了对T细胞归巢至关重要的几种趋化因子的表达,其中包括肾粘连蛋白(Npnt)。BRG1敲低阻止了肝细胞中Npnt的诱导和T淋巴细胞迁移的减弱体外,这是通过添加重组肾素来逆转的。从机理上讲,BRG1与β-catenin相互作用直接结合到p 启动子并激活 p转录。重要的是,在人类急性肝炎活检标本中检测到CD3 + T淋巴细胞浸润与肾粘连蛋白表达之间呈正相关。总之,我们的数据确定了BRG1通过激活T细胞作为T淋巴细胞运输的启动子的新作用p肝细胞中的转录。靶向BRG1-Npnt轴可能会产生新的FH治疗方案。

更新日期:2021-01-21
down
wechat
bug