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Portal, but not lobular, macrophages express matrix metalloproteinase-9: association with the ductular reaction and fibrosis in chronic hepatitis C

Authors

  • Victoria L. Gadd,

    1. Centre for Liver Disease Research, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Brisbane, Qld, Australia
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  • Michelle Melino,

    1. Centre for Liver Disease Research, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Brisbane, Qld, Australia
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  • Sandrine Roy,

    1. Diamantina Institute, The University of Queensland, Brisbane, Qld, Australia
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  • Leigh Horsfall,

    1. Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Qld, Australia
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  • Peter O'Rourke,

    1. Queensland Institute of Medical Research, Brisbane, Qld, Australia
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  • Millicent R. Williams,

    1. Centre for Liver Disease Research, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Brisbane, Qld, Australia
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  • Katharine M. Irvine,

    1. Centre for Liver Disease Research, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Brisbane, Qld, Australia
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  • Matthew J. Sweet,

    1. Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Qld, Australia
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  • Julie R. Jonsson,

    1. Centre for Liver Disease Research, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Brisbane, Qld, Australia
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  • Andrew D. Clouston,

    1. Centre for Liver Disease Research, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Brisbane, Qld, Australia
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  • Elizabeth E. Powell

    Corresponding author
    1. Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Qld, Australia
    • Centre for Liver Disease Research, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Brisbane, Qld, Australia
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Correspondence

Elizabeth Powell, Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Woolloongabba 4102 Brisbane, Qld, Australia

Tel: +61 7 32402035

Fax: +61 7 32402337

e-mail: e.powell@uq.edu.au

Abstract

Background

Liver macrophages are a heterogeneous cell population that produces factors involved in fibrogenesis and matrix turnover, including matrix metalloproteinase (MMP) -9. During liver injury, their close proximity to hepatic progenitor cells and the ductular reaction may enable them to regulate liver repair and fibrosis.

Aims

To enumerate and characterise liver macrophages in patients with chronic hepatitis C, to determine whether a distinct population of macrophages is associated with the ductular reaction and portal fibrosis.

Methods

Immunostaining for macrophage markers (CD68, CD163, CCR2), the ductular reaction (keratin-7) and MMP-9 was performed in liver biopsy sections from patients with chronic hepatitis C virus (HCV) (n = 85).

Results

Portal tracts were more densely populated with macrophages (10.5 ± 0.36 macrophages/HPF) than lobules (7.2 ± 0.16 macrophages/HPF, < 0.001) and macrophages were found in close proximity to the ductular reaction. ≥30% of portal and periductal macrophages expressed MMP-9 and these were significantly associated with increasing stage of fibrosis (rs = 0.58, 0.68, respectively, both < 0.001). In contrast, MMP-9+ macrophages were largely absent in lobular regions and non-diseased liver. Hepatic MMP-9 mRNA levels and gelatinolytic activity were significantly associated with stage of fibrosis (rs = 0.47, rs = 0.89, respectively, both < 0.001). Furthermore, a second distinct CCR2+ macrophage population was localised to the centrilobular regions and was predominantly absent from portal and periductal areas.

Conclusions

These findings demonstrate significant regional differences in macrophage phenotypes, suggesting that there are at least two populations of liver macrophages. We propose that these populations have distinct contributions to the pathogenesis of chronic HCV-related liver disease.

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