Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
Antagonism of the chemokine Ccl5 ameliorates experimental liver fibrosis in mice
Marie-Luise Berres, … , Christian Trautwein, Hermann E. Wasmuth
Marie-Luise Berres, … , Christian Trautwein, Hermann E. Wasmuth
Published October 18, 2010
Citation Information: J Clin Invest. 2010;120(11):4129-4140. https://doi.org/10.1172/JCI41732.
View: Text | PDF
Research Article Hepatology

Antagonism of the chemokine Ccl5 ameliorates experimental liver fibrosis in mice

  • Text
  • PDF
Abstract

Activation of hepatic stellate cells in response to chronic inflammation represents a crucial step in the development of liver fibrosis. However, the molecules involved in the interaction between immune cells and stellate cells remain obscure. Herein, we identify the chemokine CCL5 (also known as RANTES), which is induced in murine and human liver after injury, as a central mediator of this interaction. First, we showed in patients with liver fibrosis that CCL5 haplotypes and intrahepatic CCL5 mRNA expression were associated with severe liver fibrosis. Consistent with this, we detected Ccl5 mRNA and CCL5 protein in 2 mouse models of liver fibrosis, induced by either injection of carbon tetrachloride (CCl4) or feeding on a methionine and choline–deficient (MCD) diet. In these models, Ccl5–/– mice exhibited decreased hepatic fibrosis, with reduced stellate cell activation and immune cell infiltration. Transplantation of Ccl5-deficient bone marrow into WT recipients attenuated liver fibrosis, identifying infiltrating hematopoietic cells as the main source of Ccl5. We then showed that treatment with the CCL5 receptor antagonist Met-CCL5 inhibited cultured stellate cell migration, proliferation, and chemokine and collagen secretion. Importantly, in vivo administration of Met-CCL5 greatly ameliorated liver fibrosis in mice and was able to accelerate fibrosis regression. Our results define a successful therapeutic approach to reduce experimental liver fibrosis by antagonizing Ccl5 receptors.

Authors

Marie-Luise Berres, Rory R. Koenen, Anna Rueland, Mirko Moreno Zaldivar, Daniel Heinrichs, Hacer Sahin, Petra Schmitz, Konrad L. Streetz, Thomas Berg, Nikolaus Gassler, Ralf Weiskirchen, Amanda Proudfoot, Christian Weber, Christian Trautwein, Hermann E. Wasmuth

×

Figure 1

Association of CCL5 with liver fibrosis in humans.

Options: View larger image (or click on image) Download as PowerPoint
Association of CCL5 with liver fibrosis in humans.
(A) Haplotype analysi...
(A) Haplotype analysis of the CCL5 gene in patients with mild (stage F0/F1, 2n = 200) or advanced (stage F2–F4, 2n = 222) liver fibrosis. The overall haplotype distribution is significantly different between patients with mild fibrosis versus subjects with severe fibrosis (P = 0.01). Specifically, the third most common haplotype, CCL5_H3, is significantly more prevalent in individuals with advanced fibrosis (15.4%) compared with patients with mild fibrosis (5.9%, OR 2.83; *P < 0.05). (B) CCL5 mRNA expression is significantly elevated in subjects with advanced HCV-induced fibrosis compared with that of patients with only mild fibrosis (*P < 0.05). (C) The association of CCL5 mRNA expression with liver fibrosis is confirmed in patients with fibrosis due to NASH (*P < 0.05).
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts