AUTHOR=Arsenijevic Aleksandar , Milovanovic Jelena , Stojanovic Bojana , Djordjevic Dragana , Stanojevic Ivan , Jankovic Nenad , Vojvodic Danilo , Arsenijevic Nebojsa , Lukic Miodrag L. , Milovanovic Marija 

TITLE=Gal-3 Deficiency Suppresses Novosphyngobium aromaticivorans Inflammasome Activation and IL-17 Driven Autoimmune Cholangitis in Mice

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.01309

DOI=10.3389/fimmu.2019.01309

ISSN=1664-3224

ABSTRACT=<p>Gal-3 has the role in multiple inflammatory pathways. Multiple-hit etiology of primary biliary cholangitis (PBC) and evolving immune response at various stages of the disease includes involvement of Gal-3 in PBC pathogenesis. In this study we aimed to clarify the role of Gal-3 in <italic>Novosphingobium aromaticivorans</italic> (<italic>N. aromaticivorans</italic>) induced biliary disease. Autoimmune cholangitis was induced in mice by two intra-peritoneal injections of <italic>N. aromaticivorans</italic> within 2 weeks. The role of Gal-3 was evaluated by using Lgals3<sup>−/−</sup> mice and mice treated with Gal-3 inhibitor. The histological and serological parameters of disease, phenotype of dendritic, NK, NKT, and T cells and inflammasome expression were evaluated. Marked attenuation of the disease in Lgals3<sup>−/−</sup> and Gal-3 inhibitor, DAVANAT<sup>®</sup>, treated mice is manifested by the absence of bile duct damage, granulomas and fibrosis. Liver infiltrates of <italic>N. aromaticivorans</italic> infected wild type mice had higher incidence of pro-inflammatory macrophages, dendritic cells, NK, NKT, and T cells. Lgals3 deletion and treatment with Gal-3 inhibitor reduced inflammatory mononuclear cell infiltrate, expression of NLRP3 inflammasome in the liver infiltrates and interleukin-1β (IL-1β) production in the livers of <italic>N. aromaticivorans</italic> infected mice. <italic>In vitro</italic> stimulation of wild type peritoneal macrophages with <italic>N. aromaticivorans</italic> caused increased NLRP3 expression, caspase-1 activity and IL-1β production compared with Lgals3<sup>−/−</sup> cells. Our data highlight the importance of Gal-3 in promotion of inflammation in <italic>N. aromaticivorans</italic> induced PBC by enhancing the activation of NLRP3 inflammasome and production of IL-1β and indicate Gal-3 as possible therapeutical target in autoimmune cholangitis. Galectin-3 appears involved in inflammatory response to gut commensal leading to PBC.</p>