title: Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury.
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 (CCl(4))- 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 CCl(4)- 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 (CCl(4)) 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.
authors.affiliation: Department of Medicine III, University Hospital Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany.
authors.forename: Christer
authors.initials: C
authors.lastname: Baeck
authors.forename: Alexander
authors.initials: A
authors.lastname: Wehr
authors.forename: Karlin Raja
authors.initials: KR
authors.lastname: Karlmark
authors.forename: Felix
authors.initials: F
authors.lastname: Heymann
authors.forename: Mihael
authors.initials: M
authors.lastname: Vucur
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Gassler
authors.forename: Sebastian
authors.initials: S
authors.lastname: Huss
authors.forename: Sven
authors.initials: S
authors.lastname: Klussmann
authors.forename: Dirk
authors.initials: D
authors.lastname: Eulberg
authors.forename: Tom
authors.initials: T
authors.lastname: Luedde
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.forename: Frank
authors.initials: F
authors.lastname: Tacke
mesh_terms: D000208:Acute Disease; D000818:Animals; D052157:Aptamers, Nucleotide / Q000494:pharmacology* / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000187:drug effects / Q000502:physiology; D002251:Carbon Tetrachloride; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D056487:Chemical and Drug Induced Liver Injury, Chronic / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D002633:Chemotaxis / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005234:Fatty Liver / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000209:etiology / Q000517:prevention & control; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease
chemical_list: D052157:Aptamers, Nucleotide; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; C528578:NOX-E36-3'PEG, mouse; D002251:Carbon Tetrachloride