Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China.
Department of Anatomy, Chongqing Medical University, Chongqing, China.
Front Immunol. 2020 Feb 25;11:285. doi: 10.3389/fimmu.2020.00285. eCollection 2020.
Acute liver injury and its terminal phase, hepatic failure, trigger a series of complications, including hepatic encephalopathy, systematic inflammatory response syndrome, and multiorgan failure, with relatively high morbidity and mortality. Liver transplantation is the ultimate intervention, but the shortage of donor organs has limited clinical success. Mangiferin (MF), a xanthone glucoside, has been reported to have excellent anti-inflammatory efficacy. Here, a lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute liver injury mouse model was established to investigate the protective role of MF and the underlying mechanisms of action. Pretreatment with MF improved survival, decreased serum aminotransferase activities, and inhibited hepatic TNF-α production in LPS/D-GalN-challenged mice. Through Kupffer cell (KC) deletion by GdCl and KC adoptive transfer, KCs were confirmed to be involved in these beneficial effects of MF. MF reduced LPS-mediated TNF-α production via the suppression of the TLR4/NF-κB signaling pathway . MF promoted HO-1 expression, but the knockdown of HO-1 prevented TNF-α inhibition, suggesting that the damage-resistance effects of HO-1 occurred via the suppression of TNF-α synthesis. When HO-1-silenced KCs were transferred to the liver with KC deletion, the protective effect of MF against LPS/D-GalN-induced acute liver injury was reduced, illustrating the role of KC-derived HO-1 in the anti-injury effects of MF. Collectively, MF attenuated acute liver injury induced by LPS/D-GalN via the inhibition of TNF-α production by promoting KCs to upregulate HO-1 expression.
急性肝损伤及其终末期，即肝功能衰竭，会引发一系列并发症，包括肝性脑病、全身炎症反应综合征和多器官衰竭，其发病率和死亡率相对较高。肝移植是最终的干预手段，但供体器官的短缺限制了其临床应用。芒果苷（MF）是一种酮葡萄糖苷，已被报道具有出色的抗炎功效。在这里，我们建立了脂多糖（LPS）/D-半乳糖胺（D-GalN）诱导的急性肝损伤小鼠模型，以研究 MF 的保护作用及其作用机制。MF 预处理可提高 LPS/D-GalN 攻击小鼠的存活率，降低血清转氨酶活性，并抑制肝组织 TNF-α 的产生。通过 GdCl 敲除库普弗细胞（KC）和 KC 过继转移实验，证实 KC 参与了 MF 的这些有益作用。MF 通过抑制 TLR4/NF-κB 信号通路，减少 LPS 介导的 TNF-α 产生。MF 促进 HO-1 表达，但 HO-1 的敲低阻止了 TNF-α 的抑制，表明 HO-1 的损伤抵抗作用是通过抑制 TNF-α 的合成而发生的。当 HO-1 沉默的 KC 转移到 KC 缺失的肝脏时，MF 对 LPS/D-GalN 诱导的急性肝损伤的保护作用降低，这表明 KC 衍生的 HO-1 在 MF 的抗损伤作用中发挥作用。综上所述，MF 通过促进 KC 上调 HO-1 表达，抑制 TNF-α 产生，从而减轻 LPS/D-GalN 诱导的急性肝损伤。
