GALECTIN-1 DEACTIVATES CLASSICALLY ACTIVATED MICROGLIA AND PROTECTS FROM INFLAMMATION-INDUCED NEURODEGENERATION

STAROSSOM SC; MASCANFRONI ID; IMITOLA J; CAO L; RADDASSI KS; HERNANDEZ F; BASSIL RE; CROCI DO; CERLIANI JP; DELACOUR D; WANG Y; ELYAMAN W; KHOURY SJ; G. A.RABINOVICH

IMMUNITY

CELL PRESS

Lugar: United States; Año: 2012 vol. 37 p. 249 - 263

1074-7613

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-kB-depen- dent signaling pathways and hierarchically sup- presses 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 aug- menting its phosphatase activity and inhibitory func- tion. Gal1 was highly expressed in the acute phase of EAE, and its targeted deletion resulted in pro- nounced inflammation-induced neurodegeneration. Adoptive transfer of Gal1-secreting astrocytes or ad- ministration of recombinant Gal1 suppressed EAE through mechanisms involving microglial deactiva- tion. Thus, Gal1-glycan interactions are essential in tempering microglial activation, brain inflammation, and neurodegeneration, with critical therapeutic im- plications for MS.