Background

Liver injury is a serious threat for human health and life. Toll-like receptor 5 (TLR5) has reported to be a vital mediator in flagellin or tetrachloride (CCl4)-induced liver injury. However, the roles and etiology of TLR5 in hyperammonaemia (HA)-induced liver injury are poor defined.

Methods

HA rats were generated by intragastric administration using ammonium chloride solution. Liver status was assessed by haematoxylin and eosin (H&E) staining and measuring serum levels of liver injury markers. Immunohistochemistry (IHC) assay was used to visualize protein expression in tissues. Apoptotic index in tissues was determined by TUNEL assay. RT-qPCR assay was employed to test mRNA expression. Oxidative stress responses was assessed by detecting levels of reactive oxygen species (ROS) and related indicators. NF-κB activity was examined by TransAM NF-κB colorimetric kit.

Results

TLR5 was highly expressed in liver tissues of HA rats. TLR5 knockdown ameliorated HA-induced liver injury by inhibiting liver cell apoptosis. TLR5 depletion inhibited HA-induced pro-inflammatory cytokine expression in liver tissues, but had no effect on the infiltration of T and macrophage cells into liver tissues. TLR5 silencing impaired HA-induced oxidative stress responses in hepatocytes, but not in hepatic stellate cells (HSCs). TLR5 downregulation inhibited HA-induced activation on TLR5/NF-κB and TLR5/MAPK signaling pathways.

Conclusion

TLR5 silencing reduced HA-induced liver injury by inhibiting hepatocyte apoptosis, oxidative stress and inflammation responses via inactivating NF-κB and MAPK signals, deepening our understanding on the molecular mechanism of HA-induced liver injury and providing a potential therapeutic target for alleviating liver injury.

中文翻译：

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TLR5沉默通过使NF-κB和MAPK信号失活而抑制氧化应激和炎症反应，从而减少了高氨血症引起的肝损伤

背景

肝损伤是对人类健康和生命的严重威胁。据报道，Toll样受体5（TLR5）是鞭毛蛋白或四氯化物（CCl4）诱导的肝损伤的重要介质。但是，TLR5在高氨血症（HA）诱导的肝损伤中的作用和病因学尚不清楚。

方法

通过使用氯化铵溶液通过胃内给药来产生HA大鼠。通过苏木精和曙红（H＆E）染色并测量肝脏损伤标志物的血清水平来评估肝脏状态。免疫组织化学（IHC）测定法用于可视化组织中的蛋白质表达。通过TUNEL测定法测定组织中的细胞凋亡指数。RT-qPCR测定法用于测试mRNA表达。通过检测活性氧（ROS）和相关指标的水平来评估氧化应激反应。通过TransAMNF-κB比色试剂盒检查NF-κB活性。

结果

TLR5在HA大鼠的肝脏组织中高表达。TLR5抑制可通过抑制肝细胞凋亡改善HA诱导的肝损伤。TLR5耗竭抑制肝组织中HA诱导的促炎性细胞因子表达，但对T和巨噬细胞向肝组织的浸润没有影响。TLR5沉默削弱了肝细胞中HA诱导的氧化应激反应，但不影响肝星状细胞（HSC）中的氧化应激反应。TLR5下调抑制了HA诱导的TLR5 /NF-κB和TLR5 / MAPK信号通路的激活。

结论

TLR5沉默通过失活NF-κB和MAPK信号来抑制肝细胞凋亡，氧化应激和炎症反应，从而降低了HA诱导的肝损伤，加深了我们对HA诱导的肝损伤的分子机制的了解，并为减轻肝损伤提供了潜在的治疗靶点。