title: Galectin-1 deactivates classically activated microglia and protects from inflammation-induced neurodegeneration.
abstract: Inflammation-mediated neurodegeneration occurs in the acute and the chronic phases of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Classically activated (M1) microglia are key players mediating this process. Here, we identified Galectin-1 (Gal1), an endogenous glycan-binding protein, as a pivotal regulator of M1 microglial activation that targets the activation of p38MAPK-, CREB-, and NF-κB-dependent signaling pathways and hierarchically suppresses downstream proinflammatory mediators, such as iNOS, TNF, and CCL2. Gal1 bound to core 2 O-glycans on CD45, favoring retention of this glycoprotein on the microglial cell surface and augmenting its phosphatase activity and inhibitory function. Gal1 was highly expressed in the acute phase of EAE, and its targeted deletion resulted in pronounced inflammation-induced neurodegeneration. Adoptive transfer of Gal1-secreting astrocytes or administration of recombinant Gal1 suppressed EAE through mechanisms involving microglial deactivation. Thus, Gal1-glycan interactions are essential in tempering microglial activation, brain inflammation, and neurodegeneration, with critical therapeutic implications for MS.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Starossom
authors.forename: Ivan D
authors.initials: ID
authors.lastname: Mascanfroni
authors.forename: Jaime
authors.initials: J
authors.lastname: Imitola
authors.forename: Li
authors.initials: L
authors.lastname: Cao
authors.forename: Khadir
authors.initials: K
authors.lastname: Raddassi
authors.forename: Silvia F
authors.initials: SF
authors.lastname: Hernandez
authors.forename: Ribal
authors.initials: R
authors.lastname: Bassil
authors.forename: Diego O
authors.initials: DO
authors.lastname: Croci
authors.forename: Juan P
authors.initials: JP
authors.lastname: Cerliani
authors.forename: Delphine
authors.initials: D
authors.lastname: Delacour
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Wassim
authors.initials: W
authors.lastname: Elyaman
authors.forename: Samia J
authors.initials: SJ
authors.lastname: Khoury
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Rabinovich
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002490:Central Nervous System / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D018932:Chemokine CCL2 / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D005260:Female; D037483:Galectin 1 / Q000276:immunology* / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D009103:Multiple Sclerosis / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011134:Polysaccharides / Q000378:metabolism; D011485:Protein Binding; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D017362:Cyclic AMP Response Element-Binding Protein; D037483:Galectin 1; D015850:Interleukin-6; D016328:NF-kappa B; D011134:Polysaccharides; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; D048051:p38 Mitogen-Activated Protein Kinases; D017493:Leukocyte Common Antigens