Background: T cells reactive against beta-synuclein induce cortical grey matter inflammation and degeneration. Lung microbiota regulate the T cell-induced inflammation via microglial interferon signaling.
Hypothesis: We hypothesize that the recovery potential of the cortical grey matter upon immune attack is dictated by crucial checkpoints within and outside of the CNS that can be functionally modulated.
Strategy: We will employ an integrative approach based on multiscale imaging, cellular, microbial and molecular profiling and genetics in order to define the checkpoints which determine if the grey matter tissue regenerates from the acute inflammatory bout or becomes irreversibly damaged.
Summary
This project focuses on recovery mechanisms of the CNS tissue in the course of acute autoimmune inflammation. In the first funding period of this research network, we were able to show that the localization of the autoimmune inflammation represents a checkpoint for the failed regeneration of the CNS tissue. We found that T cells reacting against neuronal beta-synuclein induce inflammation with significant degeneration of grey matter. In contrast, myelin-specific T cells (T cells directed against myelin basic protein), which preferentially attack the white matter, caused inflammation without corresponding degeneration of the white or grey matter of the CNS (unpublished, see chapter of preliminary work). In addition, we discovered that the susceptibility to autoimmune inflammation of the white or grey matter depends on the composition of the lung microbiota (Hosang et al., 2022). Lung microbiota (bacteroides genus) brought about this control by direct regulation of the immune reactivity of the microglia in the CNS parenchyma. Thereby, interferon (IFN) signalling in microglia emerged as potential molecular pathway which tunes microglia´s disease promoting or preventing reactivity.
We therefore hypothesize that T-cell induced changes of the grey matter are crucial for the failing recovery of the CNS after repeated autoimmune bouts and that lung microbiota are external regulators of de- and regenerative processes within the CNS tissue.
In the coming funding period, based on the preliminary work, we will pursue the following aims:
Aim ❶ determine cellular and molecular mechanisms in the affected CNS tissue that prevent the recovery of the grey matter in contrast to the white matter of the CNS and Aim ❷ evaluate the relevance of the lung-brain axis and the microglial interferon signaling pathway that we have characterized as a peripheral checkpoint for controlling the regeneration of CNS tissue in acute autoimmune damage.
Our studies should reveal brain-resident and peripheral targets to prevent permanent CNS damage and/or to foster its recovery which might in perspective be exploited to develop novel therapeutic strategies.
