Galectin-1 Deactivates Classically Activated Microglia and Protects from Inflammation-Induced Neurodegeneration

Abstract

SUMMARY 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 microglia activation, targeting the activation of p38MAPK-, CREB-, and NF-κB-dependent signaling pathways and hierarchically supressing downstream pro-inflammatory 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 microglia de-activation. Thus, Gal1-glycan interactions are essential in tempering microglia activation, brain inflammation and neurodegeneration with critical therapeutic implications for MS.

TLR4-activated microglia require IFN-γ to induce severe neuronal dysfunction and death in situ

“…Strikingly, we did not observe neurotoxic effects at either structural or functional levels. This expands previous data from slice cultures (5,25,34), but contrasts with studies of neuron-glia cultures and in vivo, in which LPS exposure alone was neurotoxic (8,12,13,17,18,20,21). Several factors might account for these differences, including (i) insufficient NO levels to amplify inflammatory responses of glial cells and/or inhibit mitochondrial respiration in neurons (14,32); (ii) the neural subtype investigated (42); (iii) suppressive effects on microglia ("off" signals) from active neurons and astrocytes through cell membrane contacts, neurotransmitters, and cytokines (1, 4, 7); and (iv) the presence of antioxidative extracellular matrix components that protect neurons (43).…”

“…In primary monocultures and microglia-neuron cultures, LPS exposure alone or in combination with IFN-γ for a "booster" triggers the massive release of proinflammatory and cytotoxic factors, such as TNF-α, IL-6, and nitric oxide (NO), finally resulting in neuronal death (8,(11)(12)(13)(14)(15)(16)(17)(18). Similar effects were observed in vivo after intracerebral administration of LPS (19)(20)(21).…”

Glycan-dependent binding of galectin-1 to neuropilin-1 promotes axonal regeneration after spinal cord injury

“…13 Our recent studies revealed that Gal-1 induces microglia deactivation and prevents inflammation-induced neurodegeneration. 20 In the present study, we successfully uncoupled the microglial deactivating effect, which was observed using both WT and monomeric Gal-1 from the neuroregenerative effect, which was verified only when high concentrations of WT Gal-1 were used. This data suggest the importance of dimerization in the neuromodulatory functions of Gal-1.…”

“…Gal-1 interrupts Sema3A pathway after SCI HR Quintá et al full neuroregenerative effect through binding to NRP-1 but also contributes to deactivating microglia 20 and dampening pathogenic immune cells, 55 the coordinated action of these biological effects may lead to a better restorative process after medullar lesion.…”

“…[17][18][19] Recently, we found that Gal-1 prevents neurodegeneration and promotes neuroprotection in a model of autoimmune neuroinflammation by promoting microglia deactivation. 20 However, in spite of considerable progress, the mechanistic basis of these findings and their therapeutic implications in a setting relevant to human SCI remain unexplored.…”