title: Lipocalin 2 drives neutrophilic inflammation in alcoholic liver disease.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Austria.
authors.forename: Verena
authors.initials: V
authors.lastname: Wieser
authors.affiliation: Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology & Pneumology, Medical University Innsbruck, Austria.
authors.forename: Piotr
authors.initials: P
authors.lastname: Tymoszuk
authors.affiliation: Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Austria.
authors.forename: Timon Erik
authors.initials: TE
authors.lastname: Adolph
authors.affiliation: Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Grander
authors.affiliation: Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Austria.
authors.forename: Felix
authors.initials: F
authors.lastname: Grabherr
authors.affiliation: Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Enrich
authors.affiliation: Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Austria.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Pfister
authors.affiliation: Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Austria.
authors.forename: Lisa
authors.initials: L
authors.lastname: Lichtmanegger
authors.affiliation: Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Austria.
authors.forename: Romana
authors.initials: R
authors.lastname: Gerner
authors.affiliation: Department of Dermatology, University Hospital Zurich, Switzerland.
authors.forename: Mathias
authors.initials: M
authors.lastname: Drach
authors.affiliation: Institute of Pathology, Medical University Innsbruck, Austria.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Moser
authors.affiliation: Department of Internal Medicine II, Gastroenterology & Hepatology, Medical University Innsbruck, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Zoller
authors.affiliation: Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology & Pneumology, Medical University Innsbruck, Austria.
authors.forename: Günter
authors.initials: G
authors.lastname: Weiss
authors.affiliation: Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Austria.
authors.forename: Alexander Rupert
authors.initials: AR
authors.lastname: Moschen
authors.affiliation: Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology & Pneumology, Medical University Innsbruck, Austria.
authors.forename: Igor
authors.initials: I
authors.lastname: Theurl
authors.affiliation: Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Austria. Electronic address: herbert.tilg@i-med.ac.at.
authors.forename: Herbert
authors.initials: H
authors.lastname: Tilg
mesh_terms: D000818:Animals; D005260:Female; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D000071068:Lipocalin-2 / Q000502:physiology*; D008108:Liver Diseases, Alcoholic / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration
chemical_list: C489506:LCN2 protein, human; D000071068:Lipocalin-2; C071332:Lcn2 protein, mouse
keywords: Alcoholic liver disease; Alcoholic steatohepatitis (ASH); Hepatic inflammation; Lipocalin 2; Neutrophils