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 of myelin after demyelination occurs, but its efficiency declines during disease progression. Efficient myelin repair requires fine-tuning inflammatory responses by brain-resident micro...
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| Format: | Article |
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Frontiers Media S.A.
2023-07-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fncel.2023.1207540/full |
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| author | Lara-Jasmin Schröder Lara-Jasmin Schröder Hauke Thiesler Lina Gretenkort Thiemo Malte Möllenkamp Martin Stangel Martin Stangel Viktoria Gudi Herbert Hildebrandt Herbert Hildebrandt |
| author_facet | Lara-Jasmin Schröder Lara-Jasmin Schröder Hauke Thiesler Lina Gretenkort Thiemo Malte Möllenkamp Martin Stangel Martin Stangel Viktoria Gudi Herbert Hildebrandt Herbert Hildebrandt |
| author_sort | Lara-Jasmin Schröder |
| collection | DOAJ |
| description | Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. Spontaneous restoration of myelin after demyelination occurs, but its efficiency declines during disease progression. Efficient myelin repair requires fine-tuning inflammatory responses by brain-resident microglia and infiltrating macrophages. Accordingly, promising therapeutic strategies aim at controlling inflammation to promote remyelination. Polysialic acid (polySia) is a polymeric glycan with variable chain lengths, presented as a posttranslational modification on select protein carriers. PolySia emerges as a negative regulator of inflammatory microglia and macrophage activation and has been detected on oligodendrocyte precursors and reactive astrocytes in multiple sclerosis lesions. As shown recently, polySia-modified proteins can also be released by activated microglia, and the intrinsically released protein-bound and exogenously applied free polySia were equally able to attenuate proinflammatory microglia activation via the inhibitory immune receptor Siglec-E. In this study, we explore polySia as a candidate substance for promoting myelin regeneration by immunomodulation. Lysophosphatidylcholine-induced demyelination of organotypic cerebellar slice cultures was used as an experimental model to analyze the impact of polySia with different degrees of polymerization (DP) on remyelination and inflammation. In lysophosphatidylcholine-treated cerebellar slice cultures, polySia-positive cells were abundant during demyelination but largely reduced during remyelination. Based on the determination of DP24 as the minimal polySia chain length required for the inhibition of inflammatory BV2 microglia activation, pools with short and long polySia chains (DP8–14 and DP24–30) were generated and applied to slice cultures during remyelination. Unlike DP8–14, treatment with DP24–30 significantly improved remyelination, increased arginase-1-positive microglia ratios, and reduced the production of nitric oxide in wildtype, but not in Siglec-E-deficient slice cultures. In vitro differentiation of oligodendrocytes was not affected by DP24–30. Collectively, these results suggest a beneficial effect of exogenously applied polySia DP24–30 on remyelination by Siglec-E-dependent microglia regulation. |
| first_indexed | 2024-03-12T13:40:10Z |
| format | Article |
| id | doaj.art-62d093035d4d4638a8e6f54ae314798b |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-03-12T13:40:10Z |
| publishDate | 2023-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-62d093035d4d4638a8e6f54ae314798b2023-08-23T20:56:39ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022023-07-011710.3389/fncel.2023.12075401207540Polysialic acid promotes remyelination in cerebellar slice cultures by Siglec-E-dependent modulation of microglia polarizationLara-Jasmin Schröder0Lara-Jasmin Schröder1Hauke Thiesler2Lina Gretenkort3Thiemo Malte Möllenkamp4Martin Stangel5Martin Stangel6Viktoria Gudi7Herbert Hildebrandt8Herbert Hildebrandt9Clinic for Neurology, Hannover Medical School, Hannover, GermanyCenter for Systems Neuroscience Hannover, Hannover, GermanyInstitute of Clinical Biochemistry, Hannover Medical School, Hannover, GermanyInstitute of Clinical Biochemistry, Hannover Medical School, Hannover, GermanyClinic for Neurology, Hannover Medical School, Hannover, GermanyCenter for Systems Neuroscience Hannover, Hannover, GermanyTranslational Medicine, Novartis Institute for Biomedical Research, Novartis, Basel, SwitzerlandClinic for Neurology, Hannover Medical School, Hannover, GermanyCenter for Systems Neuroscience Hannover, Hannover, GermanyInstitute of Clinical Biochemistry, Hannover Medical School, Hannover, GermanyMultiple sclerosis is an inflammatory demyelinating disease of the central nervous system. Spontaneous restoration of myelin after demyelination occurs, but its efficiency declines during disease progression. Efficient myelin repair requires fine-tuning inflammatory responses by brain-resident microglia and infiltrating macrophages. Accordingly, promising therapeutic strategies aim at controlling inflammation to promote remyelination. Polysialic acid (polySia) is a polymeric glycan with variable chain lengths, presented as a posttranslational modification on select protein carriers. PolySia emerges as a negative regulator of inflammatory microglia and macrophage activation and has been detected on oligodendrocyte precursors and reactive astrocytes in multiple sclerosis lesions. As shown recently, polySia-modified proteins can also be released by activated microglia, and the intrinsically released protein-bound and exogenously applied free polySia were equally able to attenuate proinflammatory microglia activation via the inhibitory immune receptor Siglec-E. In this study, we explore polySia as a candidate substance for promoting myelin regeneration by immunomodulation. Lysophosphatidylcholine-induced demyelination of organotypic cerebellar slice cultures was used as an experimental model to analyze the impact of polySia with different degrees of polymerization (DP) on remyelination and inflammation. In lysophosphatidylcholine-treated cerebellar slice cultures, polySia-positive cells were abundant during demyelination but largely reduced during remyelination. Based on the determination of DP24 as the minimal polySia chain length required for the inhibition of inflammatory BV2 microglia activation, pools with short and long polySia chains (DP8–14 and DP24–30) were generated and applied to slice cultures during remyelination. Unlike DP8–14, treatment with DP24–30 significantly improved remyelination, increased arginase-1-positive microglia ratios, and reduced the production of nitric oxide in wildtype, but not in Siglec-E-deficient slice cultures. In vitro differentiation of oligodendrocytes was not affected by DP24–30. Collectively, these results suggest a beneficial effect of exogenously applied polySia DP24–30 on remyelination by Siglec-E-dependent microglia regulation.https://www.frontiersin.org/articles/10.3389/fncel.2023.1207540/fullmultiple sclerosisorganotypic cerebellar slice cultureremyelinationpolysialic acid (polySia)Siglec-Emicroglia |
| spellingShingle | Lara-Jasmin Schröder Lara-Jasmin Schröder Hauke Thiesler Lina Gretenkort Thiemo Malte Möllenkamp Martin Stangel Martin Stangel Viktoria Gudi Herbert Hildebrandt Herbert Hildebrandt Polysialic acid promotes remyelination in cerebellar slice cultures by Siglec-E-dependent modulation of microglia polarization Frontiers in Cellular Neuroscience multiple sclerosis organotypic cerebellar slice culture remyelination polysialic acid (polySia) Siglec-E microglia |
| title | Polysialic acid promotes remyelination in cerebellar slice cultures by Siglec-E-dependent modulation of microglia polarization |
| title_full | Polysialic acid promotes remyelination in cerebellar slice cultures by Siglec-E-dependent modulation of microglia polarization |
| title_fullStr | Polysialic acid promotes remyelination in cerebellar slice cultures by Siglec-E-dependent modulation of microglia polarization |
| title_full_unstemmed | Polysialic acid promotes remyelination in cerebellar slice cultures by Siglec-E-dependent modulation of microglia polarization |
| title_short | Polysialic acid promotes remyelination in cerebellar slice cultures by Siglec-E-dependent modulation of microglia polarization |
| title_sort | polysialic acid promotes remyelination in cerebellar slice cultures by siglec e dependent modulation of microglia polarization |
| topic | multiple sclerosis organotypic cerebellar slice culture remyelination polysialic acid (polySia) Siglec-E microglia |
| url | https://www.frontiersin.org/articles/10.3389/fncel.2023.1207540/full |
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