Abstract
Multiple sclerosis (MS) is a disease of the central nervous system that is characterized by inflammation and focal areas of demyelination, ultimately resulting in axonal degradation and neuronal loss. Several lines of evidence point towards a role for microglia and other brain macrophages in disease initiation and progression, but exactly how lesion formation is triggered is currently unknown. Here, we characterized early changes in MS brain tissue through transcriptomic analysis of normal appearing white matter (NAWM). We found that NAWM was characterized by enriched expression of genes associated with inflammation and cellular stress derived from brain macrophages. Single cell RNA sequencing confirmed a stress response in brain macrophages in NAWM and identified specific microglia and macrophage subsets at different stages of demyelinating lesions. We identified both phagocytic/activated microglia and CAM clusters that were associated with various MS lesion types. These overall changes in microglia and macrophages associated with lesion development in MS brain tissue may provide therapeutic targets to limit lesion progression and demyelination.
Highlights
Multiple sclerosis (MS) is an auto-immune disease damaging the central nervous system (CNS) and affects 2.8 million people worldwide [1]
A clear segregation between normal-appearing white matter (NAWM) and CWM samples was observed in PC2 and some NAWM samples grouped with white matter lesions (WMLs) samples, indicating that the NAWM in MS brains is affected even in the absence of detectable demyelination (Fig. 1b)
Biological processes associated with differentially expressed genes (DEGs) enriched in NAWM compared to CWM indicate that apoptosis, stress and inflammatory responses are present in NAWM tissues (Fig. 1d)
Summary
Multiple sclerosis (MS) is an auto-immune disease damaging the central nervous system (CNS) and affects 2.8 million people worldwide [1]. Additional clues towards the processes involved in lesion initiation are derived from the analysis of the nonlesioned areas from the CNS of affected individuals, such as normal-appearing white matter (NAWM). Analysis of gene expression levels indicated that inflammatory processes are ongoing in NAWM and might involve both microglia and astrocytes [7,8,9,10,11]. The underlying pathological mechanisms initiating and driving (inflammatory) demyelination in MS remain incompletely understood, and likely involve multiple cell types both within and outside the CNS [12]. To identify early changes in MS brain tissues, we here analyzed the transcriptional profile of NAWM tissues without apparent macrophage (either microglia or CAM) activation (in situ) and applied single-cell RNA sequencing to further determine changes in brain macrophages, including microglia
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