Kommunikation zwischen Oligodendrozyten und Mikroglia bei der Auslösung chronischer sekundärer Neuroinflammation
Zusammenfassung der Projektergebnisse
Previous studies by us have indicated that primary perturbation of oligodendrocytes by myelin gene defects results in neuroinflammation of white matter in the central nervous system. Microglial activation and CD8+ T cell recruitment contribute to axon degeneration and disease progression in mice carrying point mutations in or overexpressing the proteolipid protein (PLP). In the present project we studied how disturbed oligodendrocytes communicate with microglia to initiate detrimental neuroinflammatory reactions, focussing on the role of the myeloid cell surface molecule sialoadhesin (Sn, Siglec-1, CD169). We found that oligodendrocytes with distinct myelin gene defects display alterations in multiple signalling and cell stress pathways at early disease stages. We characterized transcriptional alterations in oligodendrocytes and microglia of myelin mutants using single-cell RNA sequencing which indicated distinct pro-inflammatory interactions between these glial cells. Using in vitro experiments, we gained evidence that MAPK signalling in oligodendrocytes drives expression of pro-inflammatory cytokines that stimulate Sn expression on microglia. This included colony stimulating factor-1 and its receptor which we showed to contribute to the pathogenesis in myelin mutant mice. We then generated PLP mutants lacking Sn to test its functional impact. This resulted in a significant attenuation of neuroinflammation, myelin and axon pathology and preserved visual function and motor coordination. Single cell transcriptomics of CD8+ T cells isolated from brains of PLP mutant mice demonstrated heterogeneity and detected a previously identified suppressor population among CNS- associated T cells. Sn deficiency resulted in an increased frequency of this regulatory population among CD8+ T cells in PLP mutants. In summary, our findings offered several important insights into disease-promoting interactions between genetically perturbed oligodendrocytes and microglia. The myeloid cell surface molecule Sn is one component promoting neuroinflammation and thereby contributes to T cell-driven axon degeneration. These findings might have important implications for some subtypes of multiple sclerosis and leukodystrophic disorders. Surprisingly, we discovered commonalities between genetic myelin disease and normal aging without defined disease, underscoring the broad relevance of these processes. Aged oligodendrocyte-lineage cells and microglia show similar but not identical transcriptional changes as in myelin mutants. Also in normal aging mice, cytotoxic CNS-associated CD8+ T cells drive axonal perturbation and neurodegeneration. Moreover, T-cell driven axon damage in aged mice can be influenced by modulating microglial activation. This might offer opportunities to interfere with or modulate these processes and help in the development of therapeutic interventions for aging-related diseases of the nervous system that are associated with neuroinflammation and neurodegeneration.
Projektbezogene Publikationen (Auswahl)
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(2018) Teriflunomide attenuates neuroinflammation-related neural damage in mice carrying human PLP1 mutations. J Neuroinflammation 15:194
Groh J, Hörner M, Martini R
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(2019) Targeting microglia attenuates neuroinflammation-related neural damage in mice carrying human PLP1 mutations. Glia 67:277-290
Groh J, Klein D, Berve K, West BL, Martini R
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(2020) Heterogeneous fate choice of genetically modulated adult neural stem cells in gray and white matter of the central nervous system. Glia 68:393-406
Beyer F, Jadasz J, Samper Agrelo I, Schira-Heinen J, Groh J, Manousi A, Bütermann C, Estrada V, Reiche L, Cantone M, Vera J, Viganò F, Dimou L, Müller HW, Hartung HP, Küry P
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(2020) Sex- and region-biased depletion of microglia/macrophages attenuates CLN1 disease in mice. J Neuroinflammation 17:323
Berve K, West BL, Martini R, Groh J
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(2021) Accumulation of cytotoxic T cells in the aged CNS leads to axon degeneration and contributes to cognitive and motor decline. Nat Aging 1:357-367
Groh J, Knöpper K, Arampatzi P, Yuan X, Lößlein L, Saliba AE, Kastenmüller W, Martini R
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(2021) Immune modulation attenuates infantile neuronal ceroid lipofuscinosis in mice before and after disease onset. Brain Commun 3:fcab047
Groh J, Berve K, Martini R
