The emerging role of galectins in (re)myelination and its potential for developing new approaches to treat multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory, demyelinating and neurodegenerative disease of the central nervous system with unknown etiology. Currently approved disease-modifying treatment modalities are immunomodulatory or immunosuppressive. While the applied drugs reduce the frequency and severity of the attacks, their efficacy to regenerate myelin membranes and to halt disease progression is limited. To achieve such therapeutic aims, understanding biological mechanisms of remyelination and identifying factors that interfere with remyelination in MS can give respective directions. Such a perspective is given by the emerging functional profile of galectins. They form a family of tissue lectins, which are potent effectors in processes as diverse as adhesion, apoptosis, immune mediator release or migration. This review focuses on endogenous and exogenous roles of galectins in glial cells such as oligodendrocytes, astrocytes and microglia in the context of de- and (re)myelination and its dysregulation in MS. Evidence is arising for a cooperation among family members so that timed expression and/or secretion of galectins-1, -3 and -4 result in modifying developmental myelination, (neuro)inflammatory processes, de- and remyelination. Dissecting the mechanisms that underlie the distinct activities of galectins and identifying galectins as target or tool to modulate remyelination have the potential to contribute to the development of novel therapeutic strategies for MS.

Galectin-4, a Negative Regulator of Oligodendrocyte Differentiation, Is Persistently Present in Axons and Microglia/Macrophages in Multiple Sclerosis Lesions.

Neuron-derived molecules are potent regulators of oligodendrocyte differentiation and myelination during brain development and upon demyelination. Their analysis will thus contribute to understanding remyelination failure in demyelinating diseases, such as multiple sclerosis (MS). Previously, we have identified neuronal galectin-4 as a novel negative soluble regulator in the timing of developmental myelination. Here, we investigated whether galectin-4 is re-expressed in axons upon demyelination to regulate the timing of remyelination. Our findings revealed that galectin-4 is transiently localized to axons in demyelinated areas upon cuprizone-induced demyelination. In contrast, in chronic demyelinated MS lesions, where remyelination fails, galectin-4 is permanently present on axons. Remarkably, microglia/macrophages in cuprizone-demyelinated areas also harbor galectin-4, as also observed in activated microglia/macrophages that are present in active MS lesions and in inflammatory infiltrates in chronic-relapsing experimental autoimmune encephalomyelitis. In vitro analysis showed that galectin-4 is effectively endocytosed by macrophages, and may scavenge galectin-4 from oligodendrocytes, and that endogenous galectin-4 levels are increased in alternatively interleukin-4-activated macrophages and microglia. Hence, similar to developmental myelination, the (re)expressed galectin-4 upon demyelination may act as factor in the timing of oligodendrocyte differentiation, while the persistent presence of galectin-4 on demyelinated axons may disrupt this fine-tuning of remyelination.