Systemic MCP-1 Levels Derive Mainly From Injured Liver and Are Associated With Complications in Cirrhosis

Front Immunol. 2020 Mar 11;11:354. doi: 10.3389/fimmu.2020.00354. eCollection 2020.

Abstract

Background and Aims: Monocyte chemotactic protein-1 (MCP-1) is a potent chemoattractant for monocytes. It is involved in pathogenesis of several inflammatory diseases. Hepatic MCP-1 is a readout of macrophage activation. While inflammation is a major driver of liver disease progression, the origin and role of circulating MCP-1 as a biomarker remains unclear. Methods: Hepatic CC-chemokine ligand 2 (CCL2) expression and F4/80 staining for Kupffer cells were measured and correlated in a mouse model of chronic liver disease (inhalative CCl4 for 7 weeks). Next, hepatic RNA levels of CCL2 were measured in explanted livers of 39 patients after transplantation and correlated with severity of disease. Changes in MCP-1 were further evaluated in a rat model of experimental cirrhosis and acute-on-chronic liver failure (ACLF). Finally, we analyzed portal and hepatic vein levels of MCP-1 in patients receiving transjugular intrahepatic portosystemic shunt insertion for complications of portal hypertension. Results: In this mouse model of fibrotic hepatitis, hepatic expression of CCL2 (P = 0.009) and the amount of F4/80 positive cells in the liver (P < 0.001) significantly increased after induction of hepatitis by CCl4 compared to control animals. Moreover, strong correlation of hepatic CCL2 expression and F4/80 positive cells were seen (P = 0.023). Furthermore, in human liver explants, hepatic transcription levels of CCL2 correlated with the MELD score of the patients, and thus disease severity (P = 0.007). The experimental model of ACLF in rats revealed significantly higher levels of MCP-1 plasma (P = 0.028) and correlation of hepatic CCL2 expression (R = 0.69, P = 0.003). Particularly, plasma MCP-1 levels did not correlate with peripheral blood monocyte CCL2 expression. Finally, higher levels of MCP-1 were observed in the hepatic compared to the portal vein (P = 0.01) in patients receiving TIPS. Similarly, a positive correlation of MCP-1 with Child-Pugh score was observed (P = 0.018). Further, in the presence of ACLF, portal and hepatic vein levels of MCP-1 were significantly higher compared to patients without ACLF (both P = 0.039). Conclusion: Circulating levels of MCP-1 mainly derive from the injured liver and are associated with severity of liver disease. Therefore, liver macrophages contribute significantly to disease progression. Circulating MCP-1 may reflect the extent of hepatic macrophage activation.

Keywords: acute-on-chronic liver failure (ACLF); decompensated liver cirrhosis; inflammation; monocyte chemotactic protein 1 (MCP-1); transjugular intrahepatic portosystemic shunt (TIPS).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute-On-Chronic Liver Failure / complications
  • Acute-On-Chronic Liver Failure / immunology
  • Animals
  • Chemical and Drug Induced Liver Injury / immunology*
  • Chemokine CCL2 / analysis
  • Chemokine CCL2 / blood*
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / physiology
  • Kupffer Cells / physiology
  • Liver / immunology*
  • Liver Cirrhosis, Experimental / complications*
  • Liver Cirrhosis, Experimental / immunology
  • Macrophage Activation*
  • Male
  • Mice
  • Mice, Inbred C57BL

Substances

  • Ccl2 protein, mouse
  • Chemokine CCL2