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.
Highlights
Unresolved hepatic inflammation is known to be a major driver of progression in liver disease [1, 2]
Monocyte chemotactic protein 1 (MCP-1) recruits peripheral monocytes to the liver and supports takeover of M1 dominant phenotype in hepatic macrophages [5]
Systemic inflammation is known to be the key mediator for the development of acute-on-chronic liver failure (ACLF), and an increase in leucocytes and Creactive protein is strongly associated with the onset of ACLF [6]
Summary
Unresolved hepatic inflammation is known to be a major driver of progression in liver disease [1, 2]. We hypothesized that levels of MCP-1 in the portal vein and hepatic transcription of CCL2 may be associated with severity of liver disease and complications of cirrhosis, including ACLF. To address this hypothesis, we measured MCP-1 transcription in explanted cirrhotic livers and MCP-1 levels in portal and hepatic venous blood from patients with decompensated cirrhosis at transjugular intrahepatic portosystemic shunt insertion (TIPS), and further confirmed our findings in animal models of cirrhosis and ACLF. Monocyte chemotactic protein-1 (MCP-1) is a potent chemoattractant for monocytes It is involved in pathogenesis of several inflammatory diseases. While inflammation is a major driver of liver disease progression, the origin and role of circulating MCP-1 as a biomarker remains unclear
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