Galectin-3 and IL-33/ST2 axis roles and interplay in diet-induced steatohepatitis

Abstract

Immune reactivity and chronic low-grade inflammation (metaflammation) play an important role in the pathogenesis of obesity-associated metabolic disorders, including type 2 diabetes and nonalcoholic fatty liver disease (NAFLD), a spectrum of diseases that include liver steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Increased adiposity and insulin resistance contribute to the progression from hepatic steatosis to NASH and fibrosis through the development of proinflammatory and profibrotic processes in the liver, including increased hepatic infiltration of innate and adaptive immune cells, altered balance of cytokines and chemokines, increased reactive oxygen species generation and hepatocellular death. Experimental models of dietary-induced NAFLD/NASH in mice on different genetic backgrounds or knockout mice with different immune reactivity are used for elucidating the pathogenesis of NASH and liver fibrosis. Galectin-3 (Gal-3), a unique chimera-type β-galactoside-binding protein of the galectin family has a regulatory role in immunometabolism and fibrogenesis. Mice deficient in Gal-3 develop pronounced adiposity, hyperglycemia and hepatic steatosis, as well as attenuated liver inflammation and fibrosis when fed an obesogenic high-fat diet. Interleukin (IL)-33, a member of the IL-1 cytokine family, mediates its effects through the ST receptor, which is present on immune and nonimmune cells and participates in immunometabolic and fibrotic disorders. Recent evidence, including our own data, suggests a protective role for the IL-33/IL-33R (ST2) signaling pathway in obesity, adipose tissue inflammation and atherosclerosis, but a profibrotic role in NASH development. The link between Gal-3 and soluble ST2 in myocardial fibrosis and heart failure progression has been demonstrated and we have recently shown that Gal-3 and the IL-33/ST2 pathway interact and both have a profibrotic role in diet-induced NASH. This review discusses the current evidence on the roles of Gal-3 and the IL-33/ST2 pathway and their interplay in obesity-associated hepatic inflammation and fibrogenesis that may be of interest in the development of therapeutic interventions to prevent and/or reverse obesity-associated hepatic inflammation and fibrosis.

Keywords: Galectin-3; Interleukin-33; Liver fibrosis; Nonalcoholic steatohepatitis; ST2.

Figure 1

Immune cells in the pathogenesis of nonalcoholic steatohepatitis. During obesity, proinflammatory M1 macrophages and Th1-type lymphocytes infiltrated in the visceral adipose tissue mediate metaflammation that triggers insulin resistance. Increased amounts of free fatty acids (FFAs) released from adipose tissue accumulate in hepatocytes, causing liver steatosis. Liver regulatory T cells suppress metabolic inflammation. Multiple signals from visceral adipose tissue and gut polarize liver resident macrophages towards M1 type, promote chemotaxis of immune cells and hepatocyte injury. Damaged hepatocytes release IL-33, which promotes release of profibrogenic IL-13 and TGF-β from IL-33R (ST2)-positive macrophages. Liver resident innate lymphoid cells type 2 (ILC2s) might also respond to IL-33 by producing IL-13. Profibrogenic cytokines activate quiescent hepatic stellate cells, which transform to myofibroblasts, the key cells involved in the development of liver fibrosis.

Figure 2

Galectin-3 and IL-33/ST2 axis in diet-induced steatohepatitis. Increased liver steatosis, but attenuated inflammation and fibrosis, in Galectin-3 knockout mice fed high-fat diet compared to diet matched C57Bl/6 wild-type mice (left panel). Decreased liver steatosis, inflammation and fibrosis in ST2 knockout mice fed high-fat diet compared to diet matched BALB/c wild-type mice.

Figure 3

Galectin-3 and IL-33/ST2 axis interaction in diet-induced steatohepatitis. Administration of IL-33 in vivo enhanced high-fat diet-induced liver fibrosis in both genotypes of mice, although to a markedly lower extent in the galectin-3 knockout mice, which was accompanied by less numerous ST2-positive myeloid cells that express IL-13. Galectin-3 plays an important regulatory role in the newly described profibrotic IL-33/ST2/IL-13 pathway in hepatic fibrosis.