Galectin-3 modulates phagocytosis-induced stellate cell activation and liver fibrosis in vivo

Joy X. Jiang, Xiangling Chen, Daniel K. Hsu, Kornelia Baghy, Nobuko Serizawa, Fiona Scott, Yoshikazu Takada, Yoko Takada, Hiroo Fukada, Jenny Chen, Sridevi Devaraj, Roger Adamson, Fu Tong Liu, Natalie J. Török

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44 Citations (Scopus)

Abstract

Hepatic stellate cells (HSC), the key fibrogenic cells of the liver, transdifferentiate into myofibroblasts upon phagocytosis of apoptotic hepatocytes. Galectin-3, a β-galactoside-binding lectin, is a regulator of the phagocytic process. In this study, our aim was to study the mechanism by which extracellular galectin-3 modulates HSC phagocytosis and activation. The role of galectin-3 in engulfment was evaluated by phagocytosis and integrin binding assays in primary HSC. Galectin-3 expression was studied by real-time PCR and enzyme-linked immunosorbent assay, and in vivo studies were done in wild-type and galectin-3 -/- mice. We found that HSC from galectin-3 -/- mice displayed decreased phagocytic activity, expression of transforming growth factor-β1, and procollagen α1(I). Recombinant galectin-3 reversed this defect, suggesting that extracellular galectin-3 is required for HSC activation. Galectin-3 facilitated the α vβ 3 heterodimer-dependent binding, indicating that galectin-3 modulates HSC phagocytosis via cross-linking this integrin and enhancing the tethering of apoptotic cells. Blocking integrin α vβ 3 resulted in decreased phagocytosis. Galectin-3 expression and release were induced in active HSC engulfing apoptotic cells, and this was mediated by the nuclear factor-κB signaling. The upregulation of galectin-3 in active HSC was further confirmed in vivo in bile duct-ligated (BDL) rats. Galectin-3 -/- mice displayed significantly decreased fibrosis, with reduced expression of α-smooth muscle actin and procollagen α1(I) following BDL. In summary, extracellular galectin-3 plays a key role in liver fibrosis by mediating HSC phagocytosis, activation, and subsequent autocrine and paracrine signaling by a feedforward mechanism.

Original languageEnglish
Pages (from-to)439-446
Number of pages8
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume302
Issue number4
DOIs
Publication statusPublished - Feb 2012

Keywords

  • Integrins
  • Liver fibrogenesis

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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  • Cite this

    Jiang, J. X., Chen, X., Hsu, D. K., Baghy, K., Serizawa, N., Scott, F., Takada, Y., Takada, Y., Fukada, H., Chen, J., Devaraj, S., Adamson, R., Liu, F. T., & Török, N. J. (2012). Galectin-3 modulates phagocytosis-induced stellate cell activation and liver fibrosis in vivo. American Journal of Physiology - Gastrointestinal and Liver Physiology, 302(4), 439-446. https://doi.org/10.1152/ajpgi.00257.2011