Liver Failure, Cirrhosis and Portal Hypertension

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

  1. Po-sung Chu1,
  2. Nobuhiro Nakamoto1,‡,*,
  3. Hirotoshi Ebinuma1,
  4. Shingo Usui1,
  5. Keita Saeki1,
  6. Atsuhiro Matsumoto1,
  7. Yohei Mikami1,
  8. Kazuo Sugiyama1,
  9. Kengo Tomita1,2,
  10. Takanori Kanai1,
  11. Hidetsugu Saito1,3,
  12. Toshifumi Hibi1,*

DOI: 10.1002/hep.26351

Additional Information

Author Information

  1. 1

    Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582 Japan

  2. 2

    Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama, 359-8513 Japan

  3. 3

    Division of Pharmacotherapeutics, Keio University School of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512 Japan

  1. ‡

    Tel: +81-3-3353-1211; Fax: +81-3-3353-6247

*Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582 Japan

  1. †

    This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.26351

  2. ‡

    Tel: +81-3-3353-1211; Fax: +81-3-3353-6247

Publication History

  1. Accepted manuscript online: 4 MAR 2013 12:25PM EST
  2. Manuscript Accepted: 19 FEB 2013
  3. Manuscript Revised: 15 FEB 2013
  4. Manuscript Received: 17 OCT 2012

Funded by

  • Japan Ministry of Education, Culture, Sports, Science and Technology
  • Keio Gijuku Academic Development Funds

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Keywords:

  • chemokine receptor;
  • cirrhosis;
  • liver injury;
  • Kupffer cells

Abstract

Chemokine receptors mediate migration of immune cells into the liver, thereby promoting liver inflammation. We recently demonstrated that C-C motif chemokine receptor (CCR) 9+ macrophages are crucial in the pathogenesis of acute liver inflammation. However, the role and underlying mechanisms of this macrophage subset in chronic liver injury and subsequent liver fibrosis are not fully understood. We confirmed tumor necrosis factor (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 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 pro-inflammatory 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. (HEPATOLOGY 2013.)

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