Polysialic acid promotes remyelination in cerebellar slice cultures by Siglec-E-dependent modulation of microglia polarization

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. Spontaneous restoration myelin after demyelination occurs, but its efficiency declines during progression. Efficient repair requires fine-tuning responses by brain-resident microglia and infiltrating macrophages. Accordingly, promising therapeutic strategies aim at controlling inflammation to promote remyelination. Polysialic acid (polySia) a polymeric glycan with variable chain lengths, presented as posttranslational modification on select protein carriers. PolySia emerges negative regulator macrophage activation has been detected oligodendrocyte precursors reactive astrocytes in multiple lesions. As shown recently, polySia-modified proteins can also be released activated microglia, intrinsically protein-bound exogenously applied free polySia were equally able attenuate proinflammatory via inhibitory immune receptor Siglec-E. In this study, we explore candidate substance for promoting regeneration immunomodulation. Lysophosphatidylcholine-induced organotypic cerebellar slice cultures was used experimental model analyze impact different degrees polymerization (DP) remyelination inflammation. lysophosphatidylcholine-treated cultures, polySia-positive cells abundant largely reduced Based determination DP24 minimal length required inhibition BV2 activation, pools short long chains (DP8–14 DP24–30) generated Unlike DP8–14, treatment DP24–30 significantly improved remyelination, increased arginase-1-positive ratios, production nitric oxide wildtype, not Siglec-E-deficient cultures. vitro differentiation oligodendrocytes affected DP24–30. Collectively, these results suggest beneficial effect Siglec-E-dependent regulation.