Differential impact of the dual CCR2/CCR5 inhibitor cenicriviroc on migration of monocyte and lymphocyte subsets in acute liver injury

PLoS One. 2017 Sep 14;12(9):e0184694. doi: 10.1371/journal.pone.0184694. eCollection 2017.

Abstract

A hallmark of acute hepatic injury is the recruitment of neutrophils, monocytes and lymphocytes, including natural killer (NK) or T cells, towards areas of inflammation. The recruitment of leukocytes from their reservoirs bone marrow or spleen into the liver is directed by chemokines such as CCL2 (for monocytes) and CCL5 (for lymphocytes). We herein elucidated the impact of chemokine receptor inhibition by the dual CCR2 and CCR5 inhibitor cenicriviroc (CVC) on the composition of myeloid and lymphoid immune cell populations in acute liver injury. CVC treatment effectively inhibited the migration of bone marrow monocytes and splenic lymphocytes (NK, CD4 T-cells) towards CCL2 or CCL5 in vitro. When liver injury was induced by an intraperitoneal injection of carbon tetrachloride (CCl4) in mice, followed by repetitive oral application of CVC, flow cytometric and unbiased t-SNE analysis of intrahepatic leukocytes demonstrated that dual CCR2/CCR5 inhibition in vivo significantly decreased numbers of monocyte derived macrophages in acutely injured livers. CVC also reduced numbers of Kupffer cells (KC) or monocyte derived macrophages with a KC-like phenotype, respectively, after injury. In contrast to the inhibitory effects in vitro, CVC had no impact on the composition of hepatic lymphoid cell populations in vivo. Effective inhibition of monocyte recruitment was associated with reduced inflammatory macrophage markers and moderately ameliorated hepatic necroses at 36h after CCl4. In conclusion, dual CCR2/CCR5 inhibition primarily translates into reduced monocyte recruitment in acute liver injury in vivo, suggesting that this strategy will be effective in reducing inflammatory macrophages in conditions of liver disease.

MeSH terms

  • Administration, Oral
  • Animals
  • Carbon Tetrachloride / toxicity
  • Cell Movement / drug effects
  • Cell Polarity
  • Chemotaxis
  • Disease Models, Animal
  • Imidazoles / administration & dosage*
  • Imidazoles / pharmacology
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / drug effects
  • Liver Failure, Acute / chemically induced
  • Liver Failure, Acute / drug therapy*
  • Liver Failure, Acute / immunology
  • Lymphocyte Subsets / cytology*
  • Lymphocyte Subsets / drug effects
  • Macrophages / cytology
  • Macrophages / drug effects*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / cytology*
  • Monocytes / drug effects
  • Sulfoxides

Substances

  • Imidazoles
  • Sulfoxides
  • cenicriviroc
  • Carbon Tetrachloride

Grants and funding

This work was supported by the German Research Foundation (DFG; Ta434/5-1 and SFB/TRR57) and the Interdisciplinary Center for Clinical Research (IZKF) Aachen. The funder provided support in the form of salaries for authors [EL], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of this author are articulated in the ‘author contributions’ section.