title: Galectin-3 controls the response of microglial cells to limit cuprizone-induced demyelination.
abstract: Galectin-3 (Gal-3) is a β-galactoside-binding lectin that plays an important role in inflammatory and neurodegenerative diseases. Cuprizone (CPZ)-induced demyelination is characterized by the loss of mature oligodendrocytes (OLG) by apoptosis, myelin sheath degeneration and recruitment of microglia and astrocytes to the lesioned area. We compared CPZ-induced demyelination of 8-week-old Lgals3(-/-) vs WT mice. Lgals3(-/-) mice displayed a similar susceptibility to CPZ-induced demyelination up to the fifth week, as evaluated by MBP immunostaining and electronic microscopy. However, OLG progenitors (OPC) generated in CPZ-treated Lgals3(-/-) mice showed diminished arborization, suggesting decreased ability of these cells to differentiate. Surprisingly, while WT mice experienced spontaneous remyelination in the fifth week of CPZ treatment-even though the CPZ diet was maintained up to sixth week-Lgals3(-/-) mice lacked this capacity and suffered continuous demyelination up to the sixth week, accompanied by pronounced astroglial activation. Moreover, after 2weeks of CPZ treatment, WT and Lgals3(-/-) mice showed lower innate anxiety as compared with respective naive mice, but only CPZ-treated Lgals3(-/-) mice showed decreased locomotor activity and exhibited spatial working memory impairment. Expression of Gal-3 increased during CPZ-induced demyelination in microglia but not in astrocytes. While CPZ-treated WT mice displayed heightened microglial activation associated with ED1 expression and pronounced upregulation of the phagocytic receptor TREM-2b, this effect was not observed in CPZ-treated Lgals3(-/-) mice which, in spite of showing an increased number of microglia, these cells evidenced caspase-3 activation. Our results indicate that Gal-3 is expressed in microglial cells to modulate their phenotype, facilitating the onset of remyelination and OLG differentiation.
authors.affiliation: Department of Biological Chemistry, School of Pharmacy and Biochemistry, University of Buenos Aires and National Research Council (CONICET), Argentina; Institute of Chemistry and Biological Physicochemistry (IQUIFIB), School of Pharmacy and Biochemistry, University of Buenos Aires and National Research Council (CONICET), Argentina.
authors.forename: H C
authors.initials: HC
authors.lastname: Hoyos
authors.affiliation: Department of Biological Chemistry, School of Pharmacy and Biochemistry, University of Buenos Aires and National Research Council (CONICET), Argentina; Institute of Chemistry and Biological Physicochemistry (IQUIFIB), School of Pharmacy and Biochemistry, University of Buenos Aires and National Research Council (CONICET), Argentina.
authors.forename: M
authors.initials: M
authors.lastname: Rinaldi
authors.affiliation: Laboratory of Immunopathology, Institute of Biology and Experimental Medicine (IBYME; CONICET), C1428 Buenos Aires, Argentina; Laboratory of Functional Glycomics, Departament of Biological Chemistry, School of Exact and Natural Sciences, University of Buenos Aires, C1428 Buenos Aires, Argentina.
authors.forename: S P
authors.initials: SP
authors.lastname: Mendez-Huergo
authors.affiliation: Department of Biological Chemistry, School of Pharmacy and Biochemistry, University of Buenos Aires and National Research Council (CONICET), Argentina; Institute of Chemistry and Biological Physicochemistry (IQUIFIB), School of Pharmacy and Biochemistry, University of Buenos Aires and National Research Council (CONICET), Argentina.
authors.forename: M
authors.initials: M
authors.lastname: Marder
authors.affiliation: Laboratory of Immunopathology, Institute of Biology and Experimental Medicine (IBYME; CONICET), C1428 Buenos Aires, Argentina; Laboratory of Functional Glycomics, Departament of Biological Chemistry, School of Exact and Natural Sciences, University of Buenos Aires, C1428 Buenos Aires, Argentina.
authors.forename: G A
authors.initials: GA
authors.lastname: Rabinovich
authors.affiliation: Department of Biological Chemistry, School of Pharmacy and Biochemistry, University of Buenos Aires and National Research Council (CONICET), Argentina; Institute of Chemistry and Biological Physicochemistry (IQUIFIB), School of Pharmacy and Biochemistry, University of Buenos Aires and National Research Council (CONICET), Argentina.
authors.forename: J M
authors.initials: JM
authors.lastname: Pasquini
authors.affiliation: Department of Biological Chemistry, School of Pharmacy and Biochemistry, University of Buenos Aires and National Research Council (CONICET), Argentina; Institute of Chemistry and Biological Physicochemistry (IQUIFIB), School of Pharmacy and Biochemistry, University of Buenos Aires and National Research Council (CONICET), Argentina. Electronic address: laupasq@yahoo.com.
authors.forename: L A
authors.initials: LA
authors.lastname: Pasquini
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D003337:Corpus Callosum / Q000648:ultrastructure*; D003471:Cuprizone / Q000633:toxicity*; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D037502:Galectin 3 / Q000235:genetics / Q000378:metabolism*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000648:ultrastructure; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects
chemical_list: D037502:Galectin 3; D003471:Cuprizone
keywords: Cuprizone; Demyelination; Galectin-3; Microglial phenotype; Oligodendroglial differentiation; TREM-2b