Galectin-3 in Inflammasome Activation and Primary Biliary Cholangitis Development

Abstract

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.

Keywords: NLRP3; galectin-3; inflammasome; primary biliary cholangitis (PBC).

Figure 1

Gal-3 in inflammasome activation and PBC development. Novosphingobium aromaticivorans infection activates innate immune cells (monocytes/macrophages) and in the presence of Gal-3 (left side) induces NLRP3 inflammasome activation. Activated macrophages produce a large amount of proinflammatory cytokines that activates NK cells and induce adequate activation of dendritic cells that are capable to activate autoreactive T lymphocytes (probably by mechanism of molecular mimicry) and induce their differentiation toward inflammatory Th1 and Th17 phenotype, and stimulate B cells to produce autoantibodies, AMA. Apoptosis of cholangiocytes induced by inflammatory process results in PDC-E2 antigen exposure in apoptotic blebs, which is recognized by produced AMA and results in antigen–antibody complex formation that contributes to cellular injury. Bile duct damage is the result of intrahepatic accumulation of inflammatory Th1 and Th17 cells, inflammatory and cytotoxic CD8 cells, activated, IL-17 producing NK and NKT cells that promote biliary injury, accompanied by autoantigen release that leads to perpetuation of autoimmune process. In the absence of Gal-3 (right side) there is no sufficient inflammasome activation followed by inadequate activation of dendritic cells and later insufficient activation of T and B lymphocytes. There is insignificant liver infiltration with inflammatory T, NK and NKT cells insufficient to trigger autoimmune process, and there is no biliary damage.