Galectin-1 deactivates classically activated microglia and protects from inflammation-induced neurodegeneration

Sarah C Starossom; Ivan D Mascanfroni; Jaime Imitola; Li Cao; Khadir Raddassi; Silvia F Hernandez; Ribal Bassil; Diego O Croci; Juan P Cerliani; Delphine Delacour; Yue Wang; Wassim Elyaman; Samia J Khoury; Gabriel A Rabinovich

doi:10.1016/j.immuni.2012.05.023

Galectin-1 deactivates classically activated microglia and protects from inflammation-induced neurodegeneration

Immunity. 2012 Aug 24;37(2):249-63. doi: 10.1016/j.immuni.2012.05.023. Epub 2012 Aug 9.

Authors

Sarah C Starossom¹, Ivan D Mascanfroni, Jaime Imitola, Li Cao, Khadir Raddassi, Silvia F Hernandez, Ribal Bassil, Diego O Croci, Juan P Cerliani, Delphine Delacour, Yue Wang, Wassim Elyaman, Samia J Khoury, Gabriel A Rabinovich

Affiliation

¹ Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Astrocytes / metabolism
Central Nervous System / immunology
Central Nervous System / metabolism
Central Nervous System / physiopathology
Chemokine CCL2 / metabolism
Cyclic AMP Response Element-Binding Protein / metabolism
Encephalomyelitis, Autoimmune, Experimental / immunology*
Encephalomyelitis, Autoimmune, Experimental / metabolism
Encephalomyelitis, Autoimmune, Experimental / therapy
Female
Galectin 1 / immunology*
Galectin 1 / metabolism
Galectin 1 / therapeutic use
Humans
Interleukin-6 / metabolism
Leukocyte Common Antigens / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Microglia / cytology
Microglia / immunology*
Microglia / metabolism
Multiple Sclerosis / immunology
Multiple Sclerosis / metabolism
Multiple Sclerosis / physiopathology
NF-kappa B / metabolism
Nitric Oxide Synthase Type II / metabolism
Polysaccharides / metabolism
Protein Binding
Tumor Necrosis Factor-alpha / metabolism
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

Chemokine CCL2
Cyclic AMP Response Element-Binding Protein
Galectin 1
Interleukin-6
NF-kappa B
Polysaccharides
Tumor Necrosis Factor-alpha
Nitric Oxide Synthase Type II
p38 Mitogen-Activated Protein Kinases
Leukocyte Common Antigens

Abstract

Publication types

MeSH terms

Substances

Grants and funding