Primary biliary cirrhosis (PBC) is a major cause of morbidity and mortality. The pathogenesis of PBC is largely unknown. Dysregulation of T cell functions is thought to play an important role however; emerging evidence has shown that not only T cells, innate immune reactions and proinflammatory macrophages also play important roles in PBC pathogenesis. Galectin-3 (gal3), a -galactoside-binding lectin is known to regulate macrophage activation and T cell functions; and gal3 also modulates liver fibrogenesis. Our preliminary data have shown that gal3 and inflammasome signaling were upregulated in human and murine PBC livers; gal3 and the inflammasome component NLRP3 were colocalized in the liver from PBC patients. Therefore, we hypothesize that galectin-3 controls the activation of inflammasome signaling in macrophages and the consequent IL-17 production by macrophages and T helper cells, leading to progressive inflammation and fibrosis in PBC. To test this hypothesis, our SPECIFIC AIMS are 1) To determine if gal3 modulates NLRP3 inflammasome activation and IL-17 production in PBC; 2) To study if gal3 mediates IL-17 production by macrophages and Th17 in PBC; 3) To determine if the deletion of gal3 is protective in PBC. In addition, we will use the Gal3 inhibitor modified citrus pectin (MCP) in the PBC murine model to assess its therapeutic effect. These studies may lead to the development of new therapeutic modalities against PBC.
Primary biliary cirrhosis (PBC) is characterized by the destruction of the intrahepatic bile ducts and inflammatory injury leading to progressive cholestasis and fibrosis. In the current study, we propose that galectin-3, an important immune regulator and a fibrosis mediator, plays a role in PBC by mediating inflammasome activation in macrophages and the subsequent IL-17 signaling cascade, contributing to inflammation and fibrosis. The findings obtained from this project may lead to the development of new therapeutic strategies in the future.
| Tian, Jijing; Yang, Guoxiang; Chen, Huan-Yuan et al. (2016) Galectin-3 regulates inflammasome activation in cholestatic liver injury. FASEB J 30:4202-4213 |
| Tian, Jijing; Feng, Yu; Fu, Hualing et al. (2015) The Aryl Hydrocarbon Receptor: A Key Bridging Molecule of External and Internal Chemical Signals. Environ Sci Technol 49:9518-31 |
