title: Gal-3 regulates the capacity of dendritic cells to promote NKT-cell-induced liver injury.
abstract: Galectin-3 (Gal-3), an endogenous lectin, exhibits pro- and anti-inflammatory effects in various disease conditions. In order to explore the role of Gal-3 in NKT-cell-dependent pathology, we induced hepatitis in C57BL/6 WT and Gal-3-deficient mice by using specific ligand for NKT cells: α-galactosylceramide, glycolipid Ag presented by CD1d. The injection of α-galactosylceramide significantly enhanced expression of Gal-3 in liver NKT and dendritic cells (DCs). Genetic deletion or selective inhibition of Gal-3 (induced by Gal-3-inhibitor TD139) abrogated the susceptibility to NKT-cell-dependent hepatitis. Blood levels of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-12) and their production by liver DCs and NKT cells were also downregulated. Genetic deletion or selective inhibition of Gal-3 alleviated influx of inflammatory CD11c(+) CD11b(+) DCs in the liver and favored tolerogenic phenotype and IL-10 production of liver NKT and DCs. Deletion of Gal-3 attenuated the capacity of DCs to support liver damage in the passive transfer experiments and to produce pro-inflammatory cytokines in vitro. Gal-3-deficient DCs failed to optimally stimulate production of pro-inflammatory cytokines in NKT cells, in vitro and in vivo. In conclusion, Gal-3 regulates the capacity of DCs to support NKT-cell-mediated liver injury, playing an important pro-inflammatory role in acute liver injury.
authors.affiliation: Centre for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.
authors.forename: Vladislav
authors.initials: V
authors.lastname: Volarevic
authors.forename: Bojana Simovic
authors.initials: BS
authors.lastname: Markovic
authors.forename: Sanja
authors.initials: S
authors.lastname: Bojic
authors.forename: Maja
authors.initials: M
authors.lastname: Stojanovic
authors.forename: Ulf
authors.initials: U
authors.lastname: Nilsson
authors.forename: Hakon
authors.initials: H
authors.lastname: Leffler
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.forename: Nebojsa
authors.initials: N
authors.lastname: Arsenijevic
authors.forename: Verica
authors.initials: V
authors.lastname: Paunovic
authors.forename: Vladimir
authors.initials: V
authors.lastname: Trajkovic
authors.forename: Miodrag L
authors.initials: ML
authors.lastname: Lukic
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000235:genetics* / Q000276:immunology; D039481:CD11b Antigen / Q000235:genetics / Q000276:immunology; D039521:CD11c Antigen / Q000235:genetics / Q000276:immunology; D002465:Cell Movement; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D005699:Galactosylceramides / Q000633:toxicity*; D037502:Galectin 3 / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D055610:Antigens, CD1d; D039481:CD11b Antigen; D039521:CD11c Antigen; C584692:CD1d antigen, mouse; D005699:Galactosylceramides; D037502:Galectin 3; C556062:IL10 protein, mouse; C485095:Lgals3 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C493154:alpha-galactosylceramide; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma
keywords: Dendritic cells; Gal-3; Hepatitis; NKT cells; Regulatory T (Treg) cells