Mouse CD11b+Kupffer Cells Recruited from Bone Marrow Accelerate Liver Regeneration after Partial Hepatectomy

TNF and Fas/FasL are vital components, not only in hepatocyte injury, but are also required for hepatocyte regeneration. Liver F4/80⁺Kupffer cells are classified into two subsets; resident radio-resistant CD68⁺cells with phagocytic and bactericidal activity, and recruited radio-sensitive CD11b⁺cells with cytokine-producing capacity. The aim of this study was to investigate the role of these Kupffer cells in the liver regeneration after partial hepatectomy (PHx) in mice. The proportion of Kupffer cell subsets in the remnant liver was examined in C57BL/6 mice by flow cytometry after PHx. To examine the role of CD11b⁺Kupffer cells/Mφ, mice were depleted of these cells before PHx by non-lethal 5 Gy irradiation with or without bone marrow transplantation (BMT) or the injection of a CCR2 (MCP-1 receptor) antagonist, and liver regeneration was evaluated. Although the proportion of CD68⁺Kupffer cells did not significantly change after PHx, the proportion of CD11b⁺Kupffer cells/Mφ and their FasL expression was greatly increased at three days after PHx, when the hepatocytes vigorously proliferate. Serum TNF and MCP-1 levels peaked one day after PHx. Irradiation eliminated the CD11b⁺Kupffer cells/Mφ for approximately two weeks in the liver, while CD68⁺Kupffer cells, NK cells and NKT cells remained, and hepatocyte regeneration was retarded. However, BMT partially restored CD11b⁺Kupffer cells/Mφ and recovered the liver regeneration. Furthermore, CCR2 antagonist treatment decreased the CD11b⁺Kupffer cells/Mφ and significantly inhibited liver regeneration. The CD11b⁺Kupffer cells/Mφ recruited from bone marrow by the MCP-1 produced by CD68⁺Kupffer cells play a pivotal role in liver regeneration via the TNF/FasL/Fas pathway after PHx.