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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 Novosphingobium aromaticivorans ( N. aromaticivorans ) induced biliary disease. Autoimmune cholangitis was induced in mice by two intra-peritoneal injections of N. aromaticivorans within 2 weeks. The role of Gal-3 was evaluated by using Lgals3 -/- 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 -/- and Gal-3 inhibitor, DAVANAT ® , treated mice is manifested by the absence of bile duct damage, granulomas and fibrosis. Liver infiltrates of N. aromaticivorans 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 N. aromaticivorans infected mice. In vitro stimulation of wild type peritoneal macrophages with N. aromaticivorans caused increased NLRP3 expression, caspase-1 activity and IL-1β production compared with Lgals3 -/- cells. Our data highlight the importance of Gal-3 in promotion of inflammation in N. aromaticivorans 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.

Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease characterized by the progressive destruction of small- and medium-sized intrahepatic bile ducts with resultant cholestasis and progressive fibrosis. Ursodeoxycholic acid and obethicholic acid are the only agents approved by the US Food and Drug Administration (FDA) for the treatment of PBC. However, for patients with advanced, end-stage PBC, liver transplantation is still the most effective treatment. Accordingly, the alternative approaches, such as mesenchymal stem cell (MSC) transplantation, have been suggested as an effective alternative therapy for these patients. Due to their immunomodulatory characteristics, MSCs are considered as promising therapeutic agents for the therapy of autoimmune liver diseases, including PBC. In this review, we have summarized the therapeutic potential of MSCs for the treatment of these diseases, emphasizing molecular and cellular mechanisms responsible for MSC-based effects in an animal model of PBC and therapeutic potential observed in recently conducted clinical trials. We have also presented several outstanding problems including safety issues regarding unwanted differentiation of transplanted MSCs which limit their therapeutic use. Efficient and safe MSC-based therapy for PBC remains a challenging issue that requires continuous cooperation between clinicians, researchers, and patients.

Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease characterized by the progressive destruction of small- and medium-sized intrahepatic bile ducts with resultant cholestasis and progressive fibrosis. Ursodeoxycholic acid and obethicholic acid are the only agents approved by the US Food and Drug Administration (FDA) for the treatment of PBC. However, for patients with advanced, end-stage PBC, liver transplantation is still the most effective treatment. Accordingly, the alternative approaches, such as mesenchymal stem cell (MSC) transplantation, have been suggested as an effective alternative therapy for these patients. Due to their immunomodulatory characteristics, MSCs are considered as promising therapeutic agents for the therapy of autoimmune liver diseases, including PBC. In this review, we have summarized the therapeutic potential of MSCs for the treatment of these diseases, emphasizing molecular and cellular mechanisms responsible for MSC-based effects in an animal model of PBC and therapeutic potential observed in recently conducted clinical trials. We have also presented several outstanding problems including safety issues regarding unwanted differentiation of transplanted MSCs which limit their therapeutic use. Efficient and safe MSC-based therapy for PBC remains a challenging issue that requires continuous cooperation between clinicians, researchers, and patients. [ABSTRACT FROM AUTHOR]

Primary biliary cholangitis (PBC) is a chronic inflammatory autoimmune liver disease characterized by inflammation and damage of small bile ducts. The NLRP3 inflammasome is a multimeric complex of proteins that after activation with various stimuli initiates an inflammatory process. Increasing data obtained from animal studies implicate the role of NLRP3 inflammasome in the pathogenesis of various diseases. Galectin-3 is a β-galactoside-binding lectin that plays important roles in various biological processes including cell proliferation, differentiation, transformation and apoptosis, pre-mRNA splicing, inflammation, fibrosis and host defense. The multilineage immune response at various stages of PBC development includes the involvement of Gal-3 in the pathogenesis of this disease. The role of Galectin-3 in the specific binding to NLRP3, and inflammasome activation in models of primary biliary cholangitis has been recently described. This review provides a brief pathogenesis of PBC and discusses the current knowledge about the role of Gal-3 in NLRP3 activation and PBC development. [ABSTRACT FROM AUTHOR]