title: Lack of galectin-3 increases Jagged1/Notch activation in bone marrow-derived dendritic cells and promotes dysregulation of T helper cell polarization.
abstract: Galectin-3, an endogenous glycan-binding protein, is abundantly expressed at sites of inflammation and immune cell activation. Although this lectin has been implicated in the control of T helper (Th) polarization, the mechanisms underlying this effect are not well understood. Here, we investigated the role of endogenous galectin-3 during the course of experimental Leishmania major infection using galectin-3-deficient (Lgals3(-/-)) mice in a BALB/c background and the involvement of Notch signaling pathway in this process. Lgals3(-/-) mice displayed an augmented, although mixed Th1/Th2 responses compared with wild-type (WT) mice. Concomitantly, lymph node and footpad lesion cells from infected Lgals3(-/-) mice showed enhanced levels of Notch signaling components (Notch-1, Jagged1, Jagged2 and Notch target gene Hes-1). Bone marrow-derived dendritic cells (BMDCs) from uninfected Lgals3(-/-) mice also displayed increased expression of the Notch ligands Delta-like-4 and Jagged1 and pro-inflammatory cytokines. In addition, activation of Notch signaling in BMDCs upon stimulation with Jagged1 was more pronounced in Lgals3(-/-) BMDCs compared to WT BMDCs; this condition resulted in increased production of IL-6 by Lgals3(-/-) BMDCs. Finally, addition of exogenous galectin-3 to Lgals3(-/-) BMDCs partially reverted the increased sensitivity to Jagged1 stimulation. Our results suggest that endogenous galectin-3 regulates Notch signaling activation in BMDCs and influences polarization of T helper responses, thus increasing susceptibility to L. major infection.
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
authors.forename: Marise L
authors.initials: ML
authors.lastname: Fermino
authors.affiliation: Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Cientificas y Técnicas, C1428 Buenos Aires, Argentina.
authors.forename: L Sebastian D
authors.initials: LS
authors.lastname: Dylon
authors.affiliation: Departamento de Biologia Celular e Molecular, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
authors.forename: Nerry T
authors.initials: NT
authors.lastname: Cecílio
authors.affiliation: Nuclear Energy Research Institute, Radiopharmacy Center, São Paulo, Brazil.
authors.forename: Sofia N
authors.initials: SN
authors.lastname: Santos
authors.affiliation: Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Cientificas y Técnicas, C1428 Buenos Aires, Argentina.
authors.forename: Marta A
authors.initials: MA
authors.lastname: Toscano
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Dias-Baruffi
authors.affiliation: Departamento de Biologia Celular e Molecular, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Roque-Barreira
authors.affiliation: Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Cientificas y Técnicas, C1428 Buenos Aires, Argentina; Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1428 Buenos Aires, Argentina.
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Rabinovich
authors.affiliation: Nuclear Energy Research Institute, Radiopharmacy Center, São Paulo, Brazil. Electronic address: ebernardes@ipen.br.
authors.forename: Emerson S
authors.initials: ES
authors.lastname: Bernardes
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D037502:Galectin 3 / Q000276:immunology* / Q000378:metabolism; D000072100:Jagged-1 Protein / Q000276:immunology*; D018320:Leishmania major; D016773:Leishmaniasis, Cutaneous / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D037502:Galectin 3; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D051880:Receptors, Notch
keywords: Galectin-3; Leishmania major; Notch signaling; T helper response