Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Austria.
Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology & Pneumology, Medical University Innsbruck, Austria.
J Hepatol. 2016 Apr;64(4):872-80. doi: 10.1016/j.jhep.2015.11.037. Epub 2015 Dec 9.
BACKGROUND & AIMS: Alcoholic steatohepatitis (ASH) is characterised by neutrophil infiltration that contributes to hepatic injury and disease. Lipocalin-2 (LCN2) was originally identified as siderophore binding peptide in neutrophils, which exerted tissue protective effects in several disease models. Here we investigate the role of LCN2 in the pathogenesis of alcohol-induced liver injury.
We compared hepatic LCN2 expression in ASH patients, alcoholic cirrhosis patients without evidence of ASH and patients with non-alcoholic fatty liver disease (NAFLD; i.e. simple steatosis). To mechanistically dissect LCN2 function in alcohol-induced liver injury, we subjected wild-type (WT) and Lcn2-deficient (Lcn2(-/-)) mice to the Lieber-DeCarli diet containing 5% ethanol (EtOH) or isocaloric maltose. Adoptive transfer experiments were performed to track neutrophil migration. Furthermore, we tested the effect of antibody-mediated LCN2 neutralisation in an acute model of ethanol-induced hepatic injury.
Patients with ASH exhibited increased hepatic LCN2 immunoreactivity compared to patients with alcoholic cirrhosis or simple steatosis, which mainly localised to neutrophils. Similarly, ethanol-fed mice exhibited increased LCN2 expression that mainly localised to leukocytes and especially neutrophils. Lcn2(-/-) mice were protected from alcoholic liver disease (ALD) as demonstrated by reduced neutrophil infiltration, liver injury and hepatic steatosis compared to WT controls. Adoptive transfers revealed that neutrophil-derived LCN2 critically determines hepatic neutrophil immigration and persistence during chronic alcohol exposure. Antibody-mediated neutralisation of LCN2 protected from hepatic injury and neutrophilic infiltration after acute alcohol challenge.
LCN2 drives ethanol-induced neutrophilic inflammation and propagates the development of ALD. Despite a critical role for LCN2 in immunity and infection, pharmacological neutralisation of LCN2 might be of promise in ALD.
酒精性脂肪性肝炎（ASH）的特征是中性粒细胞浸润，这有助于肝损伤和疾病。脂钙蛋白-2（LCN2）最初被鉴定为中性粒细胞中的铁载体结合肽，它在几种疾病模型中发挥组织保护作用。在这里，我们研究了 LCN2 在酒精诱导的肝损伤发病机制中的作用。
我们比较了 ASH 患者、无 ASH 酒精性肝硬化患者和非酒精性脂肪性肝病（NAFLD；即单纯性脂肪变性）患者的肝 LCN2 表达。为了在酒精诱导的肝损伤中机制上剖析 LCN2 的功能，我们使野生型（WT）和 Lcn2 缺陷型（Lcn2（-/-））小鼠接受含有 5%乙醇（EtOH）或等热量麦芽糖的 Lieber-DeCarli 饮食。进行了过继转移实验来跟踪中性粒细胞的迁移。此外，我们测试了抗体介导的 LCN2 中和在急性乙醇诱导的肝损伤模型中的作用。
与酒精性肝硬化或单纯性脂肪变性患者相比，ASH 患者表现出增加的肝 LCN2 免疫反应性，其主要定位于中性粒细胞。同样，乙醇喂养的小鼠表现出增加的 LCN2 表达，其主要定位于白细胞，特别是中性粒细胞。与 WT 对照相比，Lcn2（-/-）小鼠受到酒精性肝病（ALD）的保护，表现为中性粒细胞浸润、肝损伤和肝脂肪变性减少。过继转移显示，中性粒细胞衍生的 LCN2 在慢性酒精暴露期间对肝中性粒细胞浸润和持续存在具有决定性作用。抗体介导的 LCN2 中和可防止急性酒精攻击后的肝损伤和中性粒细胞浸润。
LCN2 驱动乙醇诱导的中性粒细胞炎症并促进 ALD 的发展。尽管 LCN2 在免疫和感染中具有关键作用，但 LCN2 的药理学中和可能在 ALD 中具有前景。
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