Department of Pathology, Nanjing Drum Tower Hospital Affiliated with Nanjing University School of Medicine, Nanjing, China.
Department of Gastroenterology, Nanjing Drum Tower Hospital Affiliated with Nanjing University School of Medicine, Nanjing, China.
Cell Death Dis. 2022 May 25;13(5):495. doi: 10.1038/s41419-022-04944-0.
Infiltration of eosinophils is associated with and contributes to liver regeneration. Chemotaxis of eosinophils is orchestrated by the eotaxin family of chemoattractants. We report here that expression of eotaxin-1 (referred to as eotaxin hereafter), but not that of either eotaxin-2 or eotaxin-3, were elevated, as measured by quantitative PCR and ELISA, in the proliferating murine livers compared to the quiescent livers. Similarly, exposure of primary murine hepatocytes to hepatocyte growth factor (HGF) stimulated eotaxin expression. Liver specific deletion of Brahma-related gene 1 (Brg1), a chromatin remodeling protein, attenuated eosinophil infiltration and down-regulated eotaxin expression in mice. Brg1 deficiency also blocked HGF-induced eotaxin expression in cultured hepatocytes. Further analysis revealed that Brg1 could directly bind to the proximal eotaxin promoter to activate its transcription. Mechanistically, Brg1 interacted with nuclear factor kappa B (NF-κB)/RelA to activate eotaxin transcription. NF-κB knockdown or pharmaceutical inhibition disrupted Brg1 recruitment to the eotaxin promoter and blocked eotaxin induction in hepatocytes. Adenoviral mediated over-expression of eotaxin overcame Brg1 deficiency caused delay in liver regeneration in mice. On the contrary, eotaxin depletion with RNAi or neutralizing antibodies retarded liver regeneration in mice. More important, Brg1 expression was detected to be correlated with eotaxin expression and eosinophil infiltration in human liver specimens. In conclusion, our data unveil a novel role of Brg1 as a regulator of eosinophil trafficking by activating eotaxin transcription.
嗜酸性粒细胞浸润与肝再生有关，并有助于肝再生。嗜酸性粒细胞的趋化作用是由嗜酸性粒细胞趋化因子家族协调的。我们在这里报告，与静止的肝脏相比，在增殖的鼠肝中，通过定量 PCR 和 ELISA 测量，嗜酸性粒细胞趋化因子-1（简称嗜酸性粒细胞趋化因子）的表达升高，而嗜酸性粒细胞趋化因子-2 或嗜酸性粒细胞趋化因子-3 的表达没有升高。同样，原代鼠肝细胞暴露于肝细胞生长因子 (HGF) 刺激嗜酸性粒细胞趋化因子表达。Brahma 相关基因 1 (Brg1) 是一种染色质重塑蛋白，在肝脏特异性缺失后，可减弱嗜酸性粒细胞浸润并下调小鼠肝脏中的嗜酸性粒细胞趋化因子表达。Brg1 缺乏也阻止了培养的肝细胞中 HGF 诱导的嗜酸性粒细胞趋化因子表达。进一步分析表明，Brg1 可以直接结合到嗜酸性粒细胞趋化因子启动子的近端，激活其转录。从机制上讲，Brg1 与核因子 kappa B (NF-κB)/RelA 相互作用以激活嗜酸性粒细胞趋化因子转录。NF-κB 敲低或药物抑制破坏了 Brg1 向嗜酸性粒细胞趋化因子启动子的募集，并阻止了肝细胞中嗜酸性粒细胞趋化因子的诱导。腺病毒介导的嗜酸性粒细胞趋化因子过表达克服了 Brg1 缺失导致的小鼠肝脏再生延迟。相反，用 RNAi 或中和抗体耗竭嗜酸性粒细胞趋化因子会减缓小鼠的肝脏再生。更重要的是，在人类肝脏标本中检测到 Brg1 表达与嗜酸性粒细胞趋化因子表达和嗜酸性粒细胞浸润相关。总之，我们的数据揭示了 Brg1 通过激活嗜酸性粒细胞趋化因子转录作为嗜酸性粒细胞趋化作用调节剂的新作用。
