Liver regeneration is a complex process that requires the coordinated expression of cytokines and growth factors. One well-studied model of liver regeneration is partial hepatectomy (PH), in which removal of 70% of the liver initiates compensatory hepatocyte proliferation. PH-induced liver regeneration requires the activation of resident macrophages (Kupffer cells), which produce cytokines that drive hepatocyte proliferation. Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that is known to activate macrophages and recruit monocytes during tissue injury. The goal of this study was to determine how MCP-1 contributes to macrophage activation during liver regeneration. Results indicate that hepatic and plasma MCP-1 levels increased within 12 hr after PH and correlated with hepatic recruitment of cells expressing the MCP-1 receptor, CCR2. Nevertheless, hepatocyte proliferation was comparable in MCP-1 knockout and wild-type mice, as was the expression of Kupffer cell-derived cytokines. Furthermore, hepatic recruitment of CCR2+ cells was similar in MCP-1 knockout and wild-type mice, which suggests that other chemokines may efficiently recruit CCR2+ cells in the absence of MCP-1. CCR2 appears to be required for optimal regeneration, as CCR2 knockout mice had levels of hepatocyte proliferation that were 50% lower than wild-type mice 36 hr after PH. We conclude that MCP-1 is not required for macrophage activation during PH-induced liver regeneration. Future studies should instead focus on mechanisms by which CCR2 signaling events and the hepatic recruitment of CCR2-expressing cells facilitates hepatocyte proliferation during liver regeneration
