title: Deletion of Galectin-3 Enhances Xenobiotic Induced Murine Primary Biliary Cholangitis by Facilitating Apoptosis of BECs and Release of Autoantigens.
abstract: Galectin-3 (Gal-3) is a carbohydrate binding lectin, with multiple roles in inflammatory diseases and autoimmunity including its antiapoptotic effect on epithelial cells. In particular, increased expression of Gal-3 in epithelial cells is protective from apoptosis. Based on the thesis that apoptosis of biliary epithelial cells (BECs) is critical to the pathogenesis of Primary Biliary Cholangitis (PBC), we have analyzed the role of Gal-3 in the murine model of autoimmune cholangitis. We took advantage of Gal-3 knockout mice and immunized them with a mimotope of the major mitochondrial autoantigen of PBC, 2-octynoic acid (2-OA) coupled to BSA (2OA-BSA) and evaluated the natural history of subsequent disease, compared to control wild-type mice, by measuring levels of antibodies to PDC-E2, immunohistology of liver, and expression of Gal-3. We report herein that deletion of Gal-3 significantly exacerbates autoimmune cholangitis in these mice. This is manifested by increased periportal infiltrations, bile duct damage, granulomas and fibrosis. Interestingly, the BECs of Gal-3 knockout mice had a higher response to apoptotic stimuli and there were more pro-inflammatory lymphocytes and dendritic cells (DCs) in the livers of Gal-3 knockout mice. In conclusion, Gal-3 plays a protective role in the pathways that lead to the inflammatory destruction of biliary epithelial cells.
authors.affiliation: Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Serbia.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Arsenijevic
authors.affiliation: Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Serbia.
authors.forename: Marija
authors.initials: M
authors.lastname: Milovanovic
authors.affiliation: Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Serbia.
authors.forename: Jelena
authors.initials: J
authors.lastname: Milovanovic
authors.affiliation: Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Serbia.
authors.forename: Bojana
authors.initials: B
authors.lastname: Stojanovic
authors.affiliation: Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, Serbia.
authors.forename: Natasa
authors.initials: N
authors.lastname: Zdravkovic
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA, USA.
authors.forename: Patrick S C
authors.initials: PS
authors.lastname: Leung
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA, USA.
authors.forename: Fu-Tong
authors.initials: FT
authors.lastname: Liu
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA, USA.
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.affiliation: Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Serbia.
authors.forename: Miodrag L
authors.initials: ML
authors.lastname: Lukic
mesh_terms: D000818:Animals; D017209:Apoptosis; D001324:Autoantigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015209:Cholangitis, Sclerosing / Q000276:immunology* / Q000473:pathology; D051047:Dihydrolipoyllysine-Residue Acetyltransferase / Q000276:immunology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D037502:Galectin 3 / Q000235:genetics / Q000276:immunology*; D018793:Interleukin-13 / Q000097:blood; D020381:Interleukin-17 / Q000097:blood; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D015262:Xenobiotics / Q000276:immunology
chemical_list: D001324:Autoantigens; D005229:Fatty Acids, Monounsaturated; D037502:Galectin 3; D018793:Interleukin-13; D020381:Interleukin-17; D024101:Mitochondrial Proteins; D015262:Xenobiotics; C060855:2-octynoic acid; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; C494878:Dlat protein, mouse