207 General Discussion Microglia and astrocytes as CNS innate immune cells Another goal of the thesis was to investigate the role of microglia and astrocytes as innate immune cells of the CNS as they are becoming increasingly implicated in having diverse functions and heterogeneous states in many CNS diseases. While historically, microglia were considered as the phagocytes of the brain and astrocytes as responders to damage, the rise in advanced technologies such as single cell and single nucleus RNAseq, as well as detailed pathology studies made available by a plethora of antibodies and probes has shown that microglia and astrocytes have diverse and complex functions in the CNS. In Chapter 8 we discussed the role of microglia and their heterogeneity in the white matter of the CNS. We report that microglia have regionally defined functions in the CNS which relate to development, homeostasis, ageing, and response to injury. These functions are dependent on the local needs of the CNS parenchyma and are reflected in differential transcriptomes, morphology and density of microglia numbers in the brain. Over the last years astrocytes have been recognised as critical for cell-cell interactions, homeostasis, synapse pruning and cerebral blood flow providing trophic and metabolic support for all CNS resident cells. Since many of the studies on astrocytes focus on their interactions with neurons, in Chapter 7 we have investigated the role of astrocytes as innate immune cells in the brain and their interactions with oligodendrocytes, as oligodendrocytes are essential for white matter health and homeostasis. Indeed, astrocytes produce a wide range of pro-inflammatory factors including chemokines, cytokines, increased expression of innate immune receptors and molecules68-71. We report that interactions between astrocytes and oligodendrocytes have many immunological functions where both astrocytes and oligodendrocytes are capable of secreting cytokines and reacting to them during reactive gliosis, oligodendrocyte damage, excitotoxicity and remyelination. There is a growing awareness that astrocytes are not only targets for autoimmune responses but can also initiate them in the context of neuroinflammation. Concluding remarks The objective of this thesis was to identify TSPO expression in the CNS in neurodegenerative and neuroinflammatory diseases. Identifying the cellular origin of TSPO expression in CNS diseases and investigating the role of microglia and astrocytes as innate immune cells aids in uncovering the clinical use of TSPO PET as a non-invasive biomarker for neuroinflammation. By using post-mortem studies, we characterised the cellular expressing of TSPO in the neuroinflammatory and neurodegenerative diseases MS, ALS, and AD, and their respective animal models. Our main findings of are summarised in Box 1. We hypothesised that TSPO expression is not exclusive to activated microglia but is present in a wide variety of microglia states. Additionally, we hypothesised that TSPO is also expressed by other cell types such as astrocytes in the CNS. We showed that TSPO expression in CNS diseases is a complex combination of expression by multiple cell types and states, and that TSPO PET most likely reflects a multi‐cellular neuroinflammatory reaction which is disease and context-dependent, with potential use as pharmacodynamic biomarker for therapies60,72. For example, in MS, the results emphasise that precise interpretations depend on the specific pathological context. We also hypothesised that TSPO is not upregulated in microglia once they are activated / in
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