Tu110 - Understanding Neuro-Immune Interactions in Multiple Sclerosis Brain by Single Nucleus Profiling

Multiple sclerosis (MS) is an autoimmune, neurodegenerative inflammatory disease characterized by the demyelination of neurons in the human central nervous system (CNS). Recent studies have increasingly pinpointed neuroinflammation as a crucial contributor to the pathogenesis of MS where activated non-neuronal cells, such as microglia, help drive and perpetuate an immune response within the CNS through altered transcriptional changes. However, there is still a lack of known MS-specific neuroinflammatory biomarkers involved in the activation of these pro-inflammatory pathways. We address this issue by using single-nucleus RNA sequencing (snRNA-seq) to profile MS and healthy control donor brain samples (3 MS and 3 HC) in order to develop a comprehensive and detailed perspective of the role that microglia play in the induction of neuroinflammation in MS. Using snRNA-seq, we analyzed a total of 37,533 brain cells and identified major brain cell types, including 4,796 microglial cells. Within the detected microglia, we compared MS and control brains and identified 1456 differentially expressed genes between MS and controls. We performed pathway analysis, using Ingenuity Pathway Analysis (IPA) and Gene Ontology (GO) Enrichment Analysis, and determined the canonical pathways of the microglia changes, with an upregulation of pathways involved in cellular stress and inflammation as well as a downregulation in normal neurodevelopmental pathways. Moreover, we identified 5 MS-specific microglial subclusters and their cluster-specific markers. Taken together, our study indicates that there are likely unique subgroups of microglia with specific neuroinflammatory pathways of communication that are involved in the pathogenesis of MS.