Galectin-3 deficiency prevents concanavalin A-induced hepatitis in mice

Abstract

We used concanavalin A (Con A)-induced liver injury to study the role of galectin-3 (Gal-3) in the induction of inflammatory pathology and hepatocellular damage. We tested susceptibility to Con A-induced hepatitis in galectin-3-deficient (Gal-3(-/-)) mice and analyzed the effects of pretreatment with a selective inhibitor of Gal-3 (TD139) in wild-type (WT) C57BL/6 mice, as evaluated by a liver enzyme test, quantitative histology, mononuclear cell (MNC) infiltration, cytokine production, intracellular staining of immune cells, and percentage of apoptotic MNCs in the liver. Gal-3(-/-) mice were less sensitive to Con A-induced hepatitis and had a significantly lower number of activated lymphoid and dendritic cells (DCs) in the liver. The level of tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ), and interleukin (IL)-17 and -4 in the sera and the number of TNFα-, IFNγ-, and IL-17- and -4-producing cluster of differentiation (CD)4(+) cells as well as IL-12-producing CD11c(+) DCs were lower, whereas the number of IL-10-producing CD4(+) T cells and F4/80(+) macrophages were significantly higher in livers of Gal-3(-/-) mice. Significantly higher percentages of late apoptotic Annexin V(+) propidium-idodide(+) liver-infiltrating MNCs and splenocytes were observed in Gal-3(-/-) mice, compared to WT mice. Pretreatment of WT C57BL/6 mice with TD139 led to the attenuation of liver injury and milder infiltration of IFNγ- and IL-17- and -4-producing CD4(+) T cells, as well as an increase in the total number of IL-10-producing CD4(+) T cells and F4/80(+) CD206(+) alternatively activated macrophages and prevented the apoptosis of liver-infiltrating MNCs.

Conclusions: Gal-3 plays an important proinflammatory role in Con A-induced hepatitis by promoting the activation of T lymphocytes and natural killer T cells, maturation of DCs, secretion of proinflammatory cytokines, down-regulation of M2 macrophage polarization, and apoptosis of MNCs in the liver.