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

Abstract

<b>Background and Aims:</b> 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. <b>Methods:</b> Hepatic CC-chemokine ligand 2 (<i>CCL2</i>) 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 <i>CCL2</i> 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. <b>Results:</b> In this mouse model of fibrotic hepatitis, hepatic expression of <i>CCL2</i> (<i>P</i> = 0.009) and the amount of F4/80 positive cells in the liver (<i>P</i> < 0.001) significantly increased after induction of hepatitis by CCl₄ compared to control animals. Moreover, strong correlation of hepatic <i>CCL2</i> expression and F4/80 positive cells were seen (<i>P</i> = 0.023). Furthermore, in human liver explants, hepatic transcription levels of <i>CCL2</i> correlated with the MELD score of the patients, and thus disease severity (<i>P</i> = 0.007). The experimental model of ACLF in rats revealed significantly higher levels of MCP-1 plasma (<i>P</i> = 0.028) and correlation of hepatic <i>CCL2</i> expression (<i>R</i> = 0.69, <i>P</i> = 0.003). Particularly, plasma MCP-1 levels did not correlate with peripheral blood monocyte <i>CCL2</i> expression. Finally, higher levels of MCP-1 were observed in the hepatic compared to the portal vein (<i>P</i> = 0.01) in patients receiving TIPS. Similarly, a positive correlation of MCP-1 with Child-Pugh score was observed (<i>P</i> = 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 <i>P</i> = 0.039). <b>Conclusion:</b> 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.