Galectin-3 controls the response of microglial cells to limit cuprizone-induced demyelination

H.C. HOYOS; M. RINALDI; S.P. MENDEZ-HUERGO; M. MARDER; G.A RABINOVICH; J.M. PASQUINI; L.A PASQUINI

NEUROBIOLOGY OF DISEASE

ACADEMIC PRESS INC ELSEVIER SCIENCE

Lugar: Amsterdam; Año: 2014 vol. 62 p. 441 - 455

0969-9961

Galectin-3 (Gal-3) is a â-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 byMBP 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 2 weeks 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-treatedWTmice displayed heightened microglial activation associatedwith ED1 expression and pronounced upregulation of the phagocytic receptor TREM-2b, this effectwas not observed in CPZ-treated Lgals3−/−â-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 byMBP 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 2 weeks 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-treatedWTmice displayed heightened microglial activation associatedwith ED1 expression and pronounced upregulation of the phagocytic receptor TREM-2b, this effectwas not observed in CPZ-treated Lgals3−/−Lgals3−/− vs WT mice. Lgals3−/− mice displayed a similar susceptibility to CPZ-induced demyelination up to the fifth week, as evaluated byMBP 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 2 weeks 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-treatedWTmice displayed heightened microglial activation associatedwith ED1 expression and pronounced upregulation of the phagocytic receptor TREM-2b, this effectwas not observed in CPZ-treated Lgals3−/−fifth week, as evaluated byMBP 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 2 weeks 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-treatedWTmice displayed heightened microglial activation associatedwith ED1 expression and pronounced upregulation of the phagocytic receptor TREM-2b, this effectwas not observed in CPZ-treated Lgals3−/−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 2 weeks 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-treatedWTmice displayed heightened microglial activation associatedwith ED1 expression and pronounced upregulation of the phagocytic receptor TREM-2b, this effectwas not observed in CPZ-treated Lgals3−/−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 2 weeks 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-treatedWTmice displayed heightened microglial activation associatedwith ED1 expression and pronounced upregulation of the phagocytic receptor TREM-2b, this effectwas not observed in CPZ-treated Lgals3−/−?Lgals3−/− mice lacked this capacity and suffered continuous demyelination up to the sixth week, accompanied by pronounced astroglial activation. Moreover, after 2 weeks 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-treatedWTmice displayed heightened microglial activation associatedwith ED1 expression and pronounced upregulation of the phagocytic receptor TREM-2b, this effectwas not observed in CPZ-treated Lgals3−/−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-treatedWTmice displayed heightened microglial activation associatedwith ED1 expression and pronounced upregulation of the phagocytic receptor TREM-2b, this effectwas not observed in CPZ-treated Lgals3−/−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-treatedWTmice displayed heightened microglial activation associatedwith ED1 expression and pronounced upregulation of the phagocytic receptor TREM-2b, this effectwas not observed in CPZ-treated Lgals3−/−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.