Systemic MCP-1 Levels Derive Mainly From Injured Liver and Are Associated With Complications in Cirrhosis
Alexander Queck, Hannah Bode, Frank Erhard Uschner, Maximilian Joseph Brol, Christiana Graf, Martin Schulz, Christian Jansen, Michael Praktiknjo, Robert Schierwagen, Sabine Klein, Christian Trautwein, Hermann E. Wasmuth, Marie‐Luise Berres, Jonel Trebicka, Jennifer Lehmann
Abstract
Background & 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, origin and role of circulating MCP-1 as a biomarker remains unclear. Methods: Hepatic 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 CCl4compared to control animals. Moreover, strong correlation of hepatic Ccl2 expression and F4/80 positive cells were seen (P=0.023). Also, in human liver explants, hepatic transcription levels of Ccl2 correlated with the MELD score of the patients, and thus disease severity (P=0.007). Experimental model of ACLF in rats revealed significantly higher levels of MCP-1 plasma levels in ACLF (P= 0.028) and furthermore 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 seen in the hepatic compared to the portal vein (P=0.01) in patients receiving TIPS. Similarly, positive correlation of MCP-1 with Child-Pugh score was observed (P=0.018). Also, 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.