Lipocalin 2 drives neutrophilic inflammation in alcoholic liver disease

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• 作者：Verena Wieser¹ ; ^&dagger ; ; Piotr Tymoszuk² ; ^&dagger ; ; Timon Erik Adolph¹ ; ^&dagger ; ; Christoph Grander¹ ; Felix Grabherr¹ ; Barbara Enrich¹ ; Alexandra Pfister¹ ; Lisa Lichtmanegger¹ ; Romana Gerner¹ ; Mathias Drach³ ; Patrizia Moser⁴ ; Heinz Zoller⁵ ; Gü ; nter Weiss² ; Alexander Rupert Moschen¹ ; Igor Theurl² ; Herbert Tilg¹ ; ^{herbert.tilg@i-med.ac.at" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ALD ; alcoholic liver disease ; ALT ; alanine-aminotransferase ; ASH ; alcoholic steatohepatitis ; AST ; aspartat-aminotransferase ; CFU ; colony forming units ; CRP ; C-reactive protein ; CXCL1/KC ; chemokine (C-X-C motif) ligand 1/keratinocyte chemoattractant ; CXCL2/MIP-2 ; chemokine (C-X-C motif) ligand 2/macrophage inflammatory protein 2 ; DAPI ; 4&prime ; 6-diamidino-2-phenylindole ; EtOH ; Ethanol ; FFPE ; formalin-fixed paraffin-embedded ; GAPDH ; glyceraldehyde-3-phosphate dehydrogenase ; GGT ; gamma-glutamyl-tr
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：64
• 期：4
• 页码：872-880
• 全文大小：2719 K

文摘

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.

Methods

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.

Results

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.

Conclusions

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.