Wang Qi, Wei Song, Zhou Haoming, Shen Gefenqiang, Gan Xiaojie, Zhou Shun, Qiu Jiannan, Shi Chenyu, Lu Ling
Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China.
2School of Medicine, Southeast University, Nanjing, China.
Cell Death Discov. 2019 Jul 19;5:119. doi: 10.1038/s41420-019-0198-y. eCollection 2019.
Although diabetes mellitus/hyperglycemia is a risk factor for acute liver injury, the underlying mechanism remains largely unknown. Liver-resident macrophages (Kupffer cells, KCs) and oxidative stress play critical roles in the pathogenesis of toxin-induced liver injury. Here, we evaluated the role of oxidative stress in regulating KC polarization against acetaminophen (APAP)-mediated acute liver injury in a streptozotocin-induced hyperglycemic murine model. Compared to the controls, hyperglycemic mice exhibited a significant increase in liver injury and intrahepatic inflammation. KCs obtained from hyperglycemic mice secreted higher levels of the proinflammatory factors, such as TNF-α and IL-6, lower levels of the anti-inflammatory factor IL-10. Furthermore, enhanced oxidative stress was revealed by increased levels of reactive oxygen species (ROS) in KCs from hyperglycemic mice post APAP treatment. In addition, ROS inhibitor NAC resulted in a significant decrease of ROS production in hyperglycemic KCs from mice posttreated with APAP. We also analyzed the role of hyperglycemia in macrophage M1/M2 polarization. Interestingly, we found that hyperglycemia promoted M1 polarization, but inhibited M2 polarization of KCs obtained from APAP-exposed livers, as evidenced by increased MCP-1 and inducible NO synthase (iNOS) gene induction but decreased Arg-1 and CD206 gene induction accompanied by increased STAT1 activation and decreased STAT6 activation. NAC restored Arg-1, CD206 gene induction, and STAT6 activation. To explore the mechanism how hyperglycemia regulates KCs polarization against APAP-induced acute liver injury, we examined the AMPK/PI3K/AKT signaling pathway and found decreased AMPK activation and increased AKT activation in liver and KCs from hyperglycemic mice post APAP treatment. AMPK activation by its agonist AICAR or PI3K inhibition by its antagonist LY294002 inhibited ROS production in KCs from hyperglycemic mice post APAP treatment and significantly attenuated APAP-induced liver injury in the hyperglycemic mice, compared to the control mice. Our results demonstrated that hyperglycemia exacerbated APAP-induced acute liver injury by promoting liver-resident macrophage proinflammatory response via AMPK/PI3K/AKT-mediated oxidative stress.
尽管糖尿病/高血糖是急性肝损伤的一个危险因素，但其潜在机制在很大程度上仍不清楚。肝驻留巨噬细胞（库普弗细胞，KCs）和氧化应激在毒素诱导的肝损伤发病机制中起关键作用。在此，我们在链脲佐菌素诱导的高血糖小鼠模型中评估了氧化应激在调节KCs极化以对抗对乙酰氨基酚（APAP）介导的急性肝损伤中的作用。与对照组相比，高血糖小鼠的肝损伤和肝内炎症显著增加。从高血糖小鼠获得的KCs分泌更高水平的促炎因子，如TNF-α和IL-6，抗炎因子IL-10水平较低。此外，APAP处理后，高血糖小鼠KCs中活性氧（ROS）水平升高，表明氧化应激增强。此外，ROS抑制剂NAC导致APAP处理后高血糖小鼠KCs中ROS产生显著减少。我们还分析了高血糖在巨噬细胞M1/M2极化中的作用。有趣的是，我们发现高血糖促进M1极化，但抑制从暴露于APAP的肝脏中获得的KCs的M2极化，这表现为MCP-1和诱导型一氧化氮合酶（iNOS）基因诱导增加，但Arg-1和CD206基因诱导减少，同时STAT1激活增加而STAT6激活减少。NAC恢复了Arg-1、CD206基因诱导和STAT6激活。为了探究高血糖如何调节KCs极化以对抗APAP诱导的急性肝损伤的机制，我们检测了AMPK/PI3K/AKT信号通路，发现APAP处理后高血糖小鼠肝脏和KCs中AMPK激活降低而AKT激活增加。与对照小鼠相比，其激动剂AICAR激活AMPK或其拮抗剂LY294002抑制PI3K可抑制APAP处理后高血糖小鼠KCs中的ROS产生，并显著减轻高血糖小鼠中APAP诱导的肝损伤。我们的结果表明，高血糖通过AMPK/PI3K/AKT介导的氧化应激促进肝驻留巨噬细胞促炎反应，从而加剧APAP诱导的急性肝损伤。
