Brain macrophages adopt distinct profiles prior to demyelination in multiple sclerosis

Multiple sclerosis is a disease of the central nervous system (CNS) that is characterized by inflammation and focal areas of demyelination, ultimately resulting in axonal degradation and neuronal death. Several lines of evidence point towards a role for microglia and other CNS-associated macrophages in disease initiation and progression, but exactly how lesion formation is triggered is currently unknown. Here, we characterized early changes in MS brains through transcriptomic analysis of normal appearing white matter (NAWM). We found that NAWM was already characterized by expression of inflammatory genes and that expression of genes associated with stress-response was increased, likely as a result of changes in the macrophage compartment. Single cell RNA sequencing analysis confirmed an early stress response in brain macrophages and identified specific macrophage subsets that associate with different stages of demyelinating lesions. These data provide insight into early changes in MS brains that may provide therapeutic targets in order to limit lesion development and demyelination. Overall design: Bulk RNA sequencing of 68 total tissue brain samples obtained from MS donors (normal appearing white matter and lesion) and control donors (white matter). Single-cell RNA sequencing of FACS sorted mouse brain macrophages from four treatment groups: control, cuprizone 3 weeks, cuprizone 5 weeks, remyelinated. Single-cell RNA sequencing of FACS sorted human brain macrophages from 5 donors, 3 brain regions per donor (normal appearing grey matter, normal appearing white matter and white matter lesion).