Galectin‐3 deficiency prevents concanavalin A–induced hepatitis in mice

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. (HEPATOLOGY 2012;55:1954–1964)

[1]  S. Menini,et al.  Galectin-3 ablation protects mice from diet-induced NASH: a major scavenging role for galectin-3 in liver. , 2011, Journal of hepatology.

[2]  S. Jonjić,et al.  Deletion of galectin-3 in the host attenuates metastasis of murine melanoma by modulating tumor adhesion and NK cell activity , 2011, Clinical & Experimental Metastasis.

[3]  M. Kohara,et al.  Role of interleukin‐18 in intrahepatic inflammatory cell recruitment in acute liver injury , 2011, Journal of leukocyte biology.

[4]  H. Yoon,et al.  Galectin-3 Exerts Cytokine-Like Regulatory Actions through the JAK–STAT Pathway , 2010, The Journal of Immunology.

[5]  D. Hsu,et al.  Galectin‐3 regulates T‐cell functions , 2009, Immunological reviews.

[6]  T. Pearson,et al.  End-Organ Damage in a Mouse Model of Fulminant Liver Inflammation Requires CD4+ T Cell Production of IFN-γ but Is Independent of Fas1 , 2009, The Journal of Immunology.

[7]  D. Hsu,et al.  Endogenous galectin-3 is localized in membrane lipid rafts and regulates migration of dendritic cells. , 2009, The Journal of investigative dermatology.

[8]  T. Shimosegawa,et al.  Expression of galectin‐3 involved in prognosis of patients with hepatocellular carcinoma , 2008, Hepatology research : the official journal of the Japan Society of Hepatology.

[9]  S. Forbes,et al.  Regulation of Alternative Macrophage Activation by Galectin-31 , 2008, The Journal of Immunology.

[10]  D. Hsu,et al.  The role of galectin-3 in promotion of the inflammatory response. , 2007, Drug news & perspectives.

[11]  P. Gourdy,et al.  The Pro-Th1 Cytokine IL-12 Enhances IL-4 Production by Invariant NKT Cells: Relevance for T Cell-Mediated Hepatitis1 , 2007, The Journal of Immunology.

[12]  T. Papadopoulos,et al.  IL‐10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A–induced liver injury in mice , 2007, Hepatology.

[13]  D. Hsu,et al.  Toxoplasma gondii infection reveals a novel regulatory role for galectin-3 in the interface of innate and adaptive immunity. , 2006, The American journal of pathology.

[14]  Mirna Flögel,et al.  Galectin-3: an open-ended story. , 2006, Biochimica et biophysica acta.

[15]  G. Fantuzzi,et al.  Induction of thymocyte apoptosis by systemic administration of concanavalin A in mice: role of TNF‐α, IFN‐γ and glucocorticoids , 2005 .

[16]  J. Suttles,et al.  Macrophages Sequentially Change Their Functional Phenotype in Response to Changes in Microenvironmental Influences1 , 2005, The Journal of Immunology.

[17]  D. Hsu,et al.  Critical role of galectin-3 in phagocytosis by macrophages. , 2003, The Journal of clinical investigation.

[18]  F. Brombacher,et al.  A Protective and Agonistic Function of IL-12p40 in Mycobacterial Infection1 , 2001, The Journal of Immunology.

[19]  T. Eberlein,et al.  Expression and function of galectin‐3, a β‐galactoside‐binding protein in activated T lymphocytes , 2001, Journal of Leukocyte Biology.

[20]  L. Kaer,et al.  Critical contribution of liver natural killer T cells to a murine model of hepatitis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[21]  W. Fung-Leung,et al.  Targeted disruption of the galectin-3 gene results in attenuated peritoneal inflammatory responses. , 2000, The American journal of pathology.

[22]  O. Moine,et al.  Production and role of interleukin‐10 in concanavalin A–induced hepatitis in mice , 1997, Hepatology.

[23]  H. Fujiwara,et al.  Critical involvement of interferon γ in the pathogenesis of T‐cell activation‐associated hepatitis and regulatory mechanisms of interleukin‐6 for the manifestations of hepatitis , 1996, Hepatology.

[24]  E. Chi,et al.  Expression and function of galectin-3, a beta-galactoside-binding lectin, in human monocytes and macrophages. , 1995, The American journal of pathology.

[25]  C Haanen,et al.  A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. , 1995, Journal of immunological methods.

[26]  A. Wendel,et al.  A T cell-dependent experimental liver injury in mice inducible by concanavalin A. , 1992, The Journal of clinical investigation.

[27]  N. Arsenijević,et al.  Protective role of IL-33/ST2 axis in Con A-induced hepatitis. , 2012, Journal of hepatology.

[28]  A. Ghaffar,et al.  Galectin-3 gene inactivation reduces atherosclerotic lesions and adventitial inflammation in ApoE-deficient mice. , 2008, The American journal of pathology.

[29]  G. Fantuzzi,et al.  Induction of thymocyte apoptosis by systemic administration of concanavalin A in mice: role of TNF-alpha, IFN-gamma and glucocorticoids. , 2005, European journal of immunology.

[30]  T. Eberlein,et al.  Expression and function of galectin-3, a beta-galactoside-binding protein in activated T lymphocytes. , 2001, Journal of leukocyte biology.