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

Abstract

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.

In vivo Lipopolysaccharide Tolerance Recruits CD11b⁺ Macrophages to the Liver with Enhanced Bactericidal Activity and Low Tumor Necrosis Factor-Releasing Capability, Resulting in Drastic Resistance to Lethal Septicemia

“…The TNF produced by the midzone macrophages may have been consumed by the surrounding hepatocytes in order to protect against hepatocyte injury and prevent TNF spillover into the circulation. TNF is known to be either hepatotoxic or hepa- toprotective, depending on the condition of the liver [30,31] . Consistently, TNF in the liver of LPS-tolerant mice may enhance the reactivity of CRP production to E. coli challenge (online suppl.…”

Recruited Monocytes and Type 2 Immunity Promote Lung Regeneration following Pneumonectomy

“…Recent data suggest that lung macrophages are maintained independently by self-renewal under steady-state conditions (Guilliams et al, 2013; Hashimoto et al, 2013; Hoeffel and Ginhoux, 2015; Hoeffel et al, 2015; Jakubzick et al, 2013; Perdiguero et al, 2015; Schulz et al, 2012; Suzuki et al, 2014; Yona et al, 2013). Bone marrow-derived and circulating monocytes replenish and supplement resident macrophages only after tissue macrophage depletion and during some inflammatory/regenerative states (Hashimoto et al, 2013; Yona et al, 2013), often through a mechanism involving the chemokine receptor CCR2 (Willenborg et al, 2012; Lee et al, 2015; Nishiyama et al, 2015; Ramachandran et al, 2012). Both resident and recruited macrophages are capable of proliferation at their sites of action (Davies et al, 2013).…”

Activation of imidazoline I1 receptor by moxonidine regulates the progression of liver fibrosis in the Nrf2-dependent pathway

“…Kupffer cells, the resident hepatic macrophages, play a major role in liver inflammation by releasing ROS and a variety of pro-inflammatory cytokines, which provoke HSCs activation and induce overproduction of extracellular matrix [4]. CD68, a specific KCs marker, has been widely used to monitor KCs activation during liver injury [29]. In this study, we demonstrated that MOX significantly inhibited CD68 expression in CCl 4 -treated mice.…”