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CCL20 mediates lipopolysaccharide induced liver injury and is a potential driver of inflammation and fibrosis in alcoholic hepatitis
  1. Silvia Affò1,
  2. Oriol Morales-Ibanez1,
  3. Daniel Rodrigo-Torres1,
  4. José Altamirano1,
  5. Delia Blaya1,
  6. Dianne H Dapito2,
  7. Cristina Millán1,
  8. Mar Coll1,
  9. Jorge M Caviglia2,
  10. Vicente Arroyo1,
  11. Juan Caballería1,
  12. Robert F Schwabe2,
  13. Pere Ginès1,
  14. Ramón Bataller1,3,
  15. Pau Sancho-Bru1
  1. 1Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
  2. 2Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA
  3. 3Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA
  1. Correspondence to Dr P Sancho-Bru, Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), C/Roselló, 149-153, third floor, Barcelona 08036, Spain; psancho{at}


Objective Chemokines are known to play an important role in the pathophysiology of alcoholic hepatitis (AH), a form of acute-on-chronic liver injury frequently mediated by gut derived lipopolysaccharide (LPS). In our study, we hypothesise that chemokine CCL20, one of the most upregulated chemokines in patients with AH, is implicated in the pathogenesis of AH by mediating LPS induced liver injury.

Design CCL20 gene expression and serum levels and their correlation with disease severity were assessed in patients with AH. Cellular sources of CCL20 and its biological effects were evaluated in vitro and in vivo in chronic, acute and acute-on-chronic experimental models of carbon tetrachloride and LPS induced liver injury. RNA interference technology was used to knockdown CCL20 in vivo.

Results CCL20 hepatic and serum levels were increased in patients with AH and correlated with the degree of fibrosis, portal hypertension, endotoxaemia, disease severity scores and short term mortality. Moreover, CCL20 expression was increased in animal models of liver injury and particularly under acute-on-chronic conditions. Macrophages and hepatic stellate cells (HSCs) were identified as the main CCL20 producing cell types. Silencing CCL20 in vivo reduced LPS induced aspartate aminotransferase and lactate dehydrogenase serum levels and hepatic proinflammatory and profibrogenic genes. CCL20 induced proinflammatory and profibrogenic effects in cultured primary HSCs.

Conclusions Our results suggest that CCL20 upregulation is strongly associated with LPS and may not only represent a new potential biomarker to predict outcome in patients with AH but also an important mediator linking hepatic inflammation, injury and fibrosis in AH.

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