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Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury
  1. Christer Baeck1,
  2. Alexander Wehr1,
  3. Karlin Raja Karlmark1,
  4. Felix Heymann1,
  5. Mihael Vucur1,
  6. Nikolaus Gassler2,
  7. Sebastian Huss3,
  8. Sven Klussmann4,
  9. Dirk Eulberg4,
  10. Tom Luedde1,
  11. Christian Trautwein1,
  12. Frank Tacke1
  1. 1Department of Medicine III, University Hospital Aachen, Aachen, Germany
  2. 2Institute of Pathology, University Hospital Aachen, Aachen, Germany
  3. 3Institute of Pathology, University Bonn, Bonn, Germany
  4. 4NOXXON Pharma AG, Berlin, Germany
  1. Correspondence to Frank Tacke, Department of Medicine III, University Hospital Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany; frank.tacke{at}gmx.net

Abstract

Objective Monocyte chemoattractant protein-1 (MCP-1, CCL2), the primary ligand for chemokine receptor C–C chemokine receptor 2 (CCR2), is increased in livers of patients with non-alcoholic steatohepatitis (NASH) and murine models of steatohepatitis and fibrosis. It was recently shown that monocyte/macrophage infiltration into the liver upon injury is critically regulated by the CCL2/CCR2 axis and is functionally important for perpetuating hepatic inflammation and fibrogenesis. The structured L-enantiomeric RNA oligonucleotide mNOX-E36 (a so-called Spiegelmer) potently binds and inhibits murine MCP-1. Pharmacological inhibition of MCP-1 with mNOX-E36 was investigated in two murine models of chronic liver diseases.

Methods Pharmacological inhibition of MCP-1 by thrice-weekly mNOX-E36 subcutaneously was tested in murine models of acute or chronic carbon tetrachloride (CCl4)- and methionine–choline-deficient (MCD) diet-induced chronic hepatic injury in vivo.

Results Antagonising MCP-1 by mNOX-E36 efficiently inhibited murine monocyte chemotaxis in vitro as well as migration of Gr1+ (Ly6C+) blood monocytes into the liver upon acute toxic injury in vivo. In murine models of CCl4- and MCD diet-induced hepatic injury, the infiltration of macrophages into the liver was significantly decreased in anti-MCP-1-treated mice as found by fluorescence-activated cell sorting (FACS) analysis and immunohistochemistry. In line with lower levels of intrahepatic macrophages, proinflammatory cytokines (tumour necrosis factor α, interferon γ and interleukin 6) were significantly reduced in liver tissue. Overall fibrosis progression over 6 (CCl4) or 8 weeks (MCD diet) was not significantly altered by anti-MCP-1 treatment. However, upon MCD diet challenge a lower level of fatty liver degeneration (histology score, Oil red O staining, hepatic triglyceride content, lipogenesis genes) was detected in mNOX-E36-treated animals. mNOX-E36 also ameliorated hepatic steatosis upon therapeutic administration.

Conclusions These results demonstrate the successful pharmacological inhibition of hepatic monocyte/macrophage infiltration by blocking MCP-1 during chronic liver damage in two in vivo models. The associated ameliorated steatosis development suggests that inhibition of MCP-1 is an interesting novel approach for pharmacological treatment in liver inflammation and steatohepatitis.

  • Monocyte
  • Kupffer cell
  • chemokine
  • monocyte chemoattractant protein-1
  • liver cirrhosis
  • NASH
  • liver immunology
  • cancer genetics
  • cell death
  • chronic liver disease
  • liver
  • hepatocyte
  • macrophages
  • IL-6
  • hepatitis C

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Footnotes

  • Funding This work was supported by the German Research Foundation (DFG Ta434/2-1 to FT, SFB/TRR 57) and funding from NOXXON (Berlin, Germany). DE and SK are employees of NOXXON. The funders were not involved in data analysis or interpretation.

  • Competing interests DE and SK are employees of NOXXON Pharma AG who provided part of the funding for this study.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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