C-C motif chemokine receptor 9 positive macrophages activate hepatic stellate cells and promote liver fibrosis in mice

Hakusyo Cho, Nobuhiro Nakamoto, Hirotoshi Ebinuma, Shingo Usui, Keita Saeki, Atsuhiro Matsumoto, Yohei Mikami, Kazuo Sugiyama, Kengo Tomita, Takanori Kanai, Hidetsugu Saito, Toshifumi Hibi

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Abstract

Chemokine receptors mediate migration of immune cells into the liver, thereby promoting liver inflammation. C-C motif chemokine receptor (CCR) 9+ macrophages are crucial in the pathogenesis of acute liver inflammation, but the role and underlying mechanisms of this macrophage subset in chronic liver injury and subsequent liver fibrosis are not fully understood. We confirmed that tumor necrosis factor alpha (TNF-α)-producing CCR9+ macrophages accumulated during the initiation of carbon tetrachloride (CCl4)-induced liver injury, and CCR9 deficiency attenuated the degree of liver damage. Accumulation of CCR9+ macrophages persisted prominently during the process of liver fibrosis induced by repetitive CCl4 or thioacetamide (TAA)/leptin administration. Increased CCR9 expression was also found on activated hepatic stellate cells (HSCs). Importantly, experimental liver fibrosis was significantly ameliorated in CCR9-/- mice compared with wild-type (WT) mice, assessed by α-smooth muscle actin (α-SMA) immunostain, Sirius red staining, and messenger RNA (mRNA) expression levels of α-SMA, collagen 1α1, transforming growth factor (TGF)-β1, and tissue inhibitor of metalloproteinase (TIMP)-1. Accumulated CD11b+ macrophages in CCl4-treated WT mice showed marked increases in TNF, NO synthase-2, and TGF-β1 mRNA expression compared with CCR9-/- mice, implying proinflammatory and profibrogenic properties. Hepatic CD11b+ macrophages from CCl4-treated WT mice (i.e., CCR9+ macrophages), but not CD8+ T lymphocytes or non-CD11b+ cells, significantly activated HSCs in vitro compared with those from CCR9-/- mice. TNF-α or TGF-β1 antagonism attenuated CCR9+ macrophage-induced HSC activation. Furthermore, C-C motif chemokine ligand (CCL) 25 mediated migration and, to a lesser extent, activation of HSCs in vitro. Conclusion: Accumulated CD11b+ macrophages are critical for activating HSCs through the CCR9/CCL25 axis and therefore promote liver fibrosis. CCR9 antagonism might be a novel therapeutic target for liver fibrosis.

Original languageEnglish
Pages (from-to)337-350
Number of pages14
JournalHepatology
Volume58
Issue number1
DOIs
Publication statusPublished - 2013 Jul

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CCR Receptors
Hepatic Stellate Cells
Liver Cirrhosis
Macrophages
Liver
Transforming Growth Factors
Tumor Necrosis Factor-alpha
Thioacetamide
Inflammation
CC Chemokines
Messenger RNA
Tissue Inhibitor of Metalloproteinase-1
Carbon Tetrachloride
Chemokine Receptors
Wounds and Injuries
Leptin
Nitric Oxide Synthase
Cell Movement
Smooth Muscle
Actins

ASJC Scopus subject areas

  • Hepatology

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C-C motif chemokine receptor 9 positive macrophages activate hepatic stellate cells and promote liver fibrosis in mice. / Cho, Hakusyo; Nakamoto, Nobuhiro; Ebinuma, Hirotoshi; Usui, Shingo; Saeki, Keita; Matsumoto, Atsuhiro; Mikami, Yohei; Sugiyama, Kazuo; Tomita, Kengo; Kanai, Takanori; Saito, Hidetsugu; Hibi, Toshifumi.

In: Hepatology, Vol. 58, No. 1, 07.2013, p. 337-350.

Research output: Contribution to journalArticle

Cho, H, Nakamoto, N, Ebinuma, H, Usui, S, Saeki, K, Matsumoto, A, Mikami, Y, Sugiyama, K, Tomita, K, Kanai, T, Saito, H & Hibi, T 2013, 'C-C motif chemokine receptor 9 positive macrophages activate hepatic stellate cells and promote liver fibrosis in mice', Hepatology, vol. 58, no. 1, pp. 337-350. https://doi.org/10.1002/hep.26351
Cho, Hakusyo ; Nakamoto, Nobuhiro ; Ebinuma, Hirotoshi ; Usui, Shingo ; Saeki, Keita ; Matsumoto, Atsuhiro ; Mikami, Yohei ; Sugiyama, Kazuo ; Tomita, Kengo ; Kanai, Takanori ; Saito, Hidetsugu ; Hibi, Toshifumi. / C-C motif chemokine receptor 9 positive macrophages activate hepatic stellate cells and promote liver fibrosis in mice. In: Hepatology. 2013 ; Vol. 58, No. 1. pp. 337-350.
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abstract = "Chemokine receptors mediate migration of immune cells into the liver, thereby promoting liver inflammation. C-C motif chemokine receptor (CCR) 9+ macrophages are crucial in the pathogenesis of acute liver inflammation, but the role and underlying mechanisms of this macrophage subset in chronic liver injury and subsequent liver fibrosis are not fully understood. We confirmed that tumor necrosis factor alpha (TNF-α)-producing CCR9+ macrophages accumulated during the initiation of carbon tetrachloride (CCl4)-induced liver injury, and CCR9 deficiency attenuated the degree of liver damage. Accumulation of CCR9+ macrophages persisted prominently during the process of liver fibrosis induced by repetitive CCl4 or thioacetamide (TAA)/leptin administration. Increased CCR9 expression was also found on activated hepatic stellate cells (HSCs). Importantly, experimental liver fibrosis was significantly ameliorated in CCR9-/- mice compared with wild-type (WT) mice, assessed by α-smooth muscle actin (α-SMA) immunostain, Sirius red staining, and messenger RNA (mRNA) expression levels of α-SMA, collagen 1α1, transforming growth factor (TGF)-β1, and tissue inhibitor of metalloproteinase (TIMP)-1. Accumulated CD11b+ macrophages in CCl4-treated WT mice showed marked increases in TNF, NO synthase-2, and TGF-β1 mRNA expression compared with CCR9-/- mice, implying proinflammatory and profibrogenic properties. Hepatic CD11b+ macrophages from CCl4-treated WT mice (i.e., CCR9+ macrophages), but not CD8+ T lymphocytes or non-CD11b+ cells, significantly activated HSCs in vitro compared with those from CCR9-/- mice. TNF-α or TGF-β1 antagonism attenuated CCR9+ macrophage-induced HSC activation. Furthermore, C-C motif chemokine ligand (CCL) 25 mediated migration and, to a lesser extent, activation of HSCs in vitro. Conclusion: Accumulated CD11b+ macrophages are critical for activating HSCs through the CCR9/CCL25 axis and therefore promote liver fibrosis. CCR9 antagonism might be a novel therapeutic target for liver fibrosis.",
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T1 - C-C motif chemokine receptor 9 positive macrophages activate hepatic stellate cells and promote liver fibrosis in mice

AU - Cho, Hakusyo

AU - Nakamoto, Nobuhiro

AU - Ebinuma, Hirotoshi

AU - Usui, Shingo

AU - Saeki, Keita

AU - Matsumoto, Atsuhiro

AU - Mikami, Yohei

AU - Sugiyama, Kazuo

AU - Tomita, Kengo

AU - Kanai, Takanori

AU - Saito, Hidetsugu

AU - Hibi, Toshifumi

PY - 2013/7

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N2 - Chemokine receptors mediate migration of immune cells into the liver, thereby promoting liver inflammation. C-C motif chemokine receptor (CCR) 9+ macrophages are crucial in the pathogenesis of acute liver inflammation, but the role and underlying mechanisms of this macrophage subset in chronic liver injury and subsequent liver fibrosis are not fully understood. We confirmed that tumor necrosis factor alpha (TNF-α)-producing CCR9+ macrophages accumulated during the initiation of carbon tetrachloride (CCl4)-induced liver injury, and CCR9 deficiency attenuated the degree of liver damage. Accumulation of CCR9+ macrophages persisted prominently during the process of liver fibrosis induced by repetitive CCl4 or thioacetamide (TAA)/leptin administration. Increased CCR9 expression was also found on activated hepatic stellate cells (HSCs). Importantly, experimental liver fibrosis was significantly ameliorated in CCR9-/- mice compared with wild-type (WT) mice, assessed by α-smooth muscle actin (α-SMA) immunostain, Sirius red staining, and messenger RNA (mRNA) expression levels of α-SMA, collagen 1α1, transforming growth factor (TGF)-β1, and tissue inhibitor of metalloproteinase (TIMP)-1. Accumulated CD11b+ macrophages in CCl4-treated WT mice showed marked increases in TNF, NO synthase-2, and TGF-β1 mRNA expression compared with CCR9-/- mice, implying proinflammatory and profibrogenic properties. Hepatic CD11b+ macrophages from CCl4-treated WT mice (i.e., CCR9+ macrophages), but not CD8+ T lymphocytes or non-CD11b+ cells, significantly activated HSCs in vitro compared with those from CCR9-/- mice. TNF-α or TGF-β1 antagonism attenuated CCR9+ macrophage-induced HSC activation. Furthermore, C-C motif chemokine ligand (CCL) 25 mediated migration and, to a lesser extent, activation of HSCs in vitro. Conclusion: Accumulated CD11b+ macrophages are critical for activating HSCs through the CCR9/CCL25 axis and therefore promote liver fibrosis. CCR9 antagonism might be a novel therapeutic target for liver fibrosis.

AB - Chemokine receptors mediate migration of immune cells into the liver, thereby promoting liver inflammation. C-C motif chemokine receptor (CCR) 9+ macrophages are crucial in the pathogenesis of acute liver inflammation, but the role and underlying mechanisms of this macrophage subset in chronic liver injury and subsequent liver fibrosis are not fully understood. We confirmed that tumor necrosis factor alpha (TNF-α)-producing CCR9+ macrophages accumulated during the initiation of carbon tetrachloride (CCl4)-induced liver injury, and CCR9 deficiency attenuated the degree of liver damage. Accumulation of CCR9+ macrophages persisted prominently during the process of liver fibrosis induced by repetitive CCl4 or thioacetamide (TAA)/leptin administration. Increased CCR9 expression was also found on activated hepatic stellate cells (HSCs). Importantly, experimental liver fibrosis was significantly ameliorated in CCR9-/- mice compared with wild-type (WT) mice, assessed by α-smooth muscle actin (α-SMA) immunostain, Sirius red staining, and messenger RNA (mRNA) expression levels of α-SMA, collagen 1α1, transforming growth factor (TGF)-β1, and tissue inhibitor of metalloproteinase (TIMP)-1. Accumulated CD11b+ macrophages in CCl4-treated WT mice showed marked increases in TNF, NO synthase-2, and TGF-β1 mRNA expression compared with CCR9-/- mice, implying proinflammatory and profibrogenic properties. Hepatic CD11b+ macrophages from CCl4-treated WT mice (i.e., CCR9+ macrophages), but not CD8+ T lymphocytes or non-CD11b+ cells, significantly activated HSCs in vitro compared with those from CCR9-/- mice. TNF-α or TGF-β1 antagonism attenuated CCR9+ macrophage-induced HSC activation. Furthermore, C-C motif chemokine ligand (CCL) 25 mediated migration and, to a lesser extent, activation of HSCs in vitro. Conclusion: Accumulated CD11b+ macrophages are critical for activating HSCs through the CCR9/CCL25 axis and therefore promote liver fibrosis. CCR9 antagonism might be a novel therapeutic target for liver fibrosis.

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