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Original article
Reversal of murine alcoholic steatohepatitis by pepducin-based functional blockade of interleukin-8 receptors
  1. Verena Wieser1,2,
  2. Timon E Adolph1,3,
  3. Barbara Enrich1,
  4. Athan Kuliopulos4,
  5. Arthur Kaser3,
  6. Herbert Tilg1,2,
  7. Nicole C Kaneider2,3
  1. 1Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
  2. 2Christian Doppler Research Laboratory for Gut Inflammation, Medical University Innsbruck, Innsbruck, Austria
  3. 3Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
  4. 4Center for Hemostasis and Thrombosis Research, Molecular Oncology Research Institute, Tufts Medical Center, Tufts University School of Medicine, Massachusetts, USA
  1. Correspondence to Dr Nicole C Kaneider, Wellcome Trust Career Re-Entry Fellow, Division of Gastroenterology & Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, UK; nk428{at}cam.ac.uk

Abstract

Objective Alcoholic steatohepatitis is a life-threatening condition with short-term mortality up to 40%. It features hepatic neutrophil infiltration and blood neutrophilia, and may evolve from ethanol-induced breakdown of the enteric barrier and consequent bacteraemia. Signalling through CXCR1/2 G-protein-coupled-receptors (GPCRs), the interleukin (IL)-8 receptors, is critical for the recruitment and activation of neutrophils. We have developed short lipopeptides (pepducins), which inhibit post-ligand GPCR activation precisely targeting individual GPCRs.

Design Experimental alcoholic liver disease was induced by administering alcohol and a Lieber–DeCarli high-fat diet. CXCR1/2 GPCRs were blocked via pepducins either from onset of the experiment or after disease was fully established. Hepatic inflammatory infiltration, hepatocyte lipid accumulation and overall survival were assessed as primary outcome parameters. Neutrophil activation was assessed by myeloperoxidase activity and liver cell damage by aspartate aminotransferase and alanine aminotransferase plasma levels. Chemotaxis assays were performed to identify chemoattractant signals derived from alcohol-exposed hepatocytes.

Results Here, we show that experimental alcoholic liver disease is driven by CXCR1/2-dependent activation of neutrophils. CXCR1/2-specific pepducins not only protected mice from liver inflammation, weight loss and mortality associated with experimental alcoholic liver disease, but therapeutic administration cured disease and prevented further mortality in fully established disease. Hepatic neutrophil infiltration and triglyceride accumulation was abrogated by CXCR1/2 blockade. Moreover, CXCL-1 plasma levels were decreased with the pepducin therapy as was the transcription of hepatic IL-1β mRNA.

Conclusions We propose that high circulating IL-8 in human alcoholic hepatitis may cause pathogenic overzealous neutrophil activation, and therapeutic blockade via pepducins merits clinical study.

  • ALCOHOLIC LIVER DISEASE
  • IMMUNE-MEDIATED LIVER DAMAGE
  • INTERLEUKIN 8
  • LEUKOCYTES

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

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