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

Abstract

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.

Gut–Liver Axis and Inflammasome Activation in Cholangiocyte Pathophysiology

“…Previous studies have shown that Galectin-3, a lectin produced by macrophages, may activate the NLRP3 inflammasome in the liver and contribute to collagen deposition in a murine model of cholestasis [98]. Interestingly, treatment of mice with Davanat, a registered inhibitor of Galectin-3 that is currently being studied in clinical trials, determined a significant reduction in inflammasome activation and biliary damage in a model of autoimmune cholangitis [99]. Vardenafil, a phosphodiesterase-5 inhibitor, has been shown to significantly reduce the expression of Nlrp3 and inflammasome components in a cholestatic murine model induced by lithocolic acid administration [100].…”

Galectin-3 in Inflammasome Activation and Primary Biliary Cholangitis Development

“…We used the model of PBC induced by Novosphingobium aromaticivorans infection of C57BL/6 mice to further explore the role of Gal-3 in PBC pathogenesis and its role in NLRP3 inflammasome activation. We found significantly higher percentage of NLRP3 expressing dendritic cells and macrophages, higher production of IL-1β and higher expression of NLRP3 and ASC in the livers of Gal-3 +/+ mice early after infection with N. aromaticivorans in comparison with the group of Gal-3 −/− mice [ 155 ].…”

NLRP3 receptor contributes to protection against experimental antigen-mediated cholangitis

“…The role of NLRP3 in driving Th-17 responses in the GI tract needs to be clarified since Tian et al reported that activation of NLRP3 promotes IL-17 production in autoimmune cholestasis generated by a dominant negative isoform of the TGFβ receptor II (TGFβRII) [21]. In line with this, Arsenijevic et al recently described a central role of NLRP3 in driving IL-17 in an infectious model of cholangitis as well [22]. In contrast, NLRP3-deficient mice induced with colitis released more IL-17 [9].…”