title: Galectin-3 modulates phagocytosis-induced stellate cell activation and liver fibrosis in vivo.
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(v)β(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(v)β(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.
authors.affiliation: UC Davis Medical Center, PSSB, Sacramento, CA 95817, USA.
authors.forename: Joy X
authors.initials: JX
authors.lastname: Jiang
authors.forename: Xiangling
authors.initials: X
authors.lastname: Chen
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Hsu
authors.forename: Kornelia
authors.initials: K
authors.lastname: Baghy
authors.forename: Nobuko
authors.initials: N
authors.lastname: Serizawa
authors.forename: Fiona
authors.initials: F
authors.lastname: Scott
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Takada
authors.forename: Yoko
authors.initials: Y
authors.lastname: Takada
authors.forename: Hiroo
authors.initials: H
authors.lastname: Fukada
authors.forename: Jenny
authors.initials: J
authors.lastname: Chen
authors.forename: Sridevi
authors.initials: S
authors.lastname: Devaraj
authors.forename: Roger
authors.initials: R
authors.lastname: Adamson
authors.forename: Fu-Tong
authors.initials: FT
authors.lastname: Liu
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Török
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D037502:Galectin 3 / Q000235:genetics / Q000378:metabolism*; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010587:Phagocytosis / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D037502:Galectin 3; D016328:NF-kappa B