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

Nishiyama K, Nakashima H, Ikarashi M, Kinoshita M, Nakashima M, Aosasa S, Seki S, Yamamoto J - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, National Defense Medical College, Namiki 3-2, Tokorozawa, Saitama, Japan 359-8513.

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.

No MeSH data available.


Related in: MedlinePlus

The changes in the proportions of CD11b Kupffer cells after PHx in mice with or without CCR2 antagonist administration(A). Representative flow cytometric data for CD11b Kupffer cells three days after PHx with or without treatment with a CCR2 antagonist (B). The mitotic figures of hepatocytes (C, D). The remnant liver weight recovery in mice with or without CCR2 antagonist treatment after PHx (E). Three to five mice were examined at each of the indicated time points. (*P < .05 vs control).
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pone.0136774.g005: The changes in the proportions of CD11b Kupffer cells after PHx in mice with or without CCR2 antagonist administration(A). Representative flow cytometric data for CD11b Kupffer cells three days after PHx with or without treatment with a CCR2 antagonist (B). The mitotic figures of hepatocytes (C, D). The remnant liver weight recovery in mice with or without CCR2 antagonist treatment after PHx (E). Three to five mice were examined at each of the indicated time points. (*P < .05 vs control).

Mentions: To further confirm the role of CD11b+ Kupffer cells/Mφ, we examined the effects of an antagonist of CCR2 [35, 36], which is a ligand of MCP-1 produced by CD68+ Kupffer cells that leads to the accumulation of CD11b+ Kupffer cells/Mφ into the liver from the periphery and BM [23, 24]. The results showed that the continuous administration of CCR2 antagonist greatly decreased the accumulation of CD11b+ Kupffer cells/Mφ (Fig 5A and 5B) and also decreased the hepatocyte proliferation after PHx (Fig 5C and 5D). Consequently, the liver regeneration was significantly impaired by CCR2 antagonist treatment, especially early after PHx (at one and three days post-PHx) (Fig 5E).


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

Nishiyama K, Nakashima H, Ikarashi M, Kinoshita M, Nakashima M, Aosasa S, Seki S, Yamamoto J - PLoS ONE (2015)

The changes in the proportions of CD11b Kupffer cells after PHx in mice with or without CCR2 antagonist administration(A). Representative flow cytometric data for CD11b Kupffer cells three days after PHx with or without treatment with a CCR2 antagonist (B). The mitotic figures of hepatocytes (C, D). The remnant liver weight recovery in mice with or without CCR2 antagonist treatment after PHx (E). Three to five mice were examined at each of the indicated time points. (*P < .05 vs control).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4557907&req=5

pone.0136774.g005: The changes in the proportions of CD11b Kupffer cells after PHx in mice with or without CCR2 antagonist administration(A). Representative flow cytometric data for CD11b Kupffer cells three days after PHx with or without treatment with a CCR2 antagonist (B). The mitotic figures of hepatocytes (C, D). The remnant liver weight recovery in mice with or without CCR2 antagonist treatment after PHx (E). Three to five mice were examined at each of the indicated time points. (*P < .05 vs control).
Mentions: To further confirm the role of CD11b+ Kupffer cells/Mφ, we examined the effects of an antagonist of CCR2 [35, 36], which is a ligand of MCP-1 produced by CD68+ Kupffer cells that leads to the accumulation of CD11b+ Kupffer cells/Mφ into the liver from the periphery and BM [23, 24]. The results showed that the continuous administration of CCR2 antagonist greatly decreased the accumulation of CD11b+ Kupffer cells/Mφ (Fig 5A and 5B) and also decreased the hepatocyte proliferation after PHx (Fig 5C and 5D). Consequently, the liver regeneration was significantly impaired by CCR2 antagonist treatment, especially early after PHx (at one and three days post-PHx) (Fig 5E).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, National Defense Medical College, Namiki 3-2, Tokorozawa, Saitama, Japan 359-8513.

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.

No MeSH data available.


Related in: MedlinePlus