Background: In autoantibody-mediated neuro-inflammation, pathology often spreads quickly between glial cells due to unknown reasons.

Hypothesis: We hypothesize that both topo-logical and molecular glia-glia interactions could represent checkpoints to curtail spread or stimulate repair of autoimmune pathology.

Strategy: We will use in vivo imaging in transgenic mice, single cell and spatial transcriptomics, as well as experimental modulation of possible glial communication pathways and corroboration in human tissue, to explore ways to curtail spreading glial pathology.

Summary

Neuromyelitis optica spectrum disorder (NMOSD) and MOGantibody disease (MOGAD) are prototypical antibody-mediated CNS gliopathies, during which antibodies against astrocyte or oligodendrocyte proteins initiate inflammatory lesions characterized by astrocyte loss, demyelination and axonal damage. Data from others and us demonstrate that the lesion microenvironment is crucially impacted by a close interaction between astrocytes and oligodendrocytes, underlying the initial spread of pathology from one glial cell type to another and determining the extent of lesion recovery. During the first funding period, we identified an acute demyelination-independent form of axon pathology governed by cytoskeletal remodelling and characterized the dynamics of astrocyte repopulation, as well as the resulting chronic astrocyte phenotypes. Furthermore, we noted a swift spread of cellular pathology between glial cells, as well as an incomplete astrocytic repopulation – suggesting that interactions between glial cells might represent important checkpoints both of lesion formation, as well as of lesion recovery.

In the second funding period, to explore such checkpoints of inter-glial communication, we will use in vivo imaging in new mouse models of acute and chronic NMOSD/MOGAD-lesions in white and grey matter. These models will be combined with manipulations guided by integrated single cell and spatial transcriptome analysis of mouse and human tissues to dissect the interaction between astrocytes, oligodendrocytes and neurons during CNS neuroinflammation triggered by glial cell-specific autoantibodies. We want to achieve the following overarching aims:

❶ Identify checkpoints of glia-to-glia pathology spread in early NMOSD/MOGAD lesionsHere, we want to use in vivo imaging in preclinical mouse models to explore, how targeting one glial cell type for complement-mediated lysis with NMOSD- or MOGAD-related autoantibodies affects the non-targeted class of macroglial cells (i.e. oligodendrocytes in NMOSD-related and astrocytes in MOGAD-realted models). After identifying possible checkpoints that control glia-to-glia pathology spread, we will confirm hallmarks of these checkpoints in human tissue and target identified mechanisms to limit glial injury and pathology spread.

❷ Define chronic astrocyte-to-oligodendrocyte interaction checkpoints during lesion repair. In work related to this aim, we will investigate whether during NMOSD lesion chronification the extent and phenotypic characteristics of repopulating astrocytes determines the choice between recovery vs. progressive degeneration of the axon-myelin unit. A particular focus will be on the modes of remyelination, and the dependence on astrocyte repopulation.