AUTHOR=Queck Alexander , Bode Hannah , Uschner Frank E. , Brol Maximilian J. , Graf Christiana , Schulz Martin , Jansen Christian , Praktiknjo Michael , Schierwagen Robert , Klein Sabine , Trautwein Christian , Wasmuth Hermann E. , Berres Marie-Luise , Trebicka Jonel , Lehmann Jennifer 

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

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.00354

DOI=10.3389/fimmu.2020.00354

ISSN=1664-3224

ABSTRACT=<p><bold>Background and Aims:</bold> 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.</p><p><bold>Methods:</bold> Hepatic CC-chemokine ligand 2 (<italic>CCL2</italic>) expression and F4/80 staining for Kupffer cells were measured and correlated in a mouse model of chronic liver disease (inhalative CCl<sub>4</sub> for 7 weeks). Next, hepatic RNA levels of <italic>CCL2</italic> 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.</p><p><bold>Results:</bold> In this mouse model of fibrotic hepatitis, hepatic expression of <italic>CCL2</italic> (<italic>P</italic> = 0.009) and the amount of F4/80 positive cells in the liver (<italic>P</italic> &lt; 0.001) significantly increased after induction of hepatitis by CCl<sub>4</sub> compared to control animals. Moreover, strong correlation of hepatic <italic>CCL2</italic> expression and F4/80 positive cells were seen (<italic>P</italic> = 0.023). Furthermore, in human liver explants, hepatic transcription levels of <italic>CCL2</italic> correlated with the MELD score of the patients, and thus disease severity (<italic>P</italic> = 0.007). The experimental model of ACLF in rats revealed significantly higher levels of MCP-1 plasma (<italic>P</italic> = 0.028) and correlation of hepatic <italic>CCL2</italic> expression (<italic>R</italic> = 0.69, <italic>P</italic> = 0.003). Particularly, plasma MCP-1 levels did not correlate with peripheral blood monocyte <italic>CCL2</italic> expression. Finally, higher levels of MCP-1 were observed in the hepatic compared to the portal vein (<italic>P</italic> = 0.01) in patients receiving TIPS. Similarly, a positive correlation of MCP-1 with Child-Pugh score was observed (<italic>P</italic> = 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 <italic>P</italic> = 0.039).</p><p><bold>Conclusion:</bold> 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.</p>