Microglial states determine lesion dynamics in multiple sclerosis

Summary paragraph Multiple sclerosis (MS) is a neuroinflammatory disease of the central nervous system, characterized by demyelinating lesions 1. Lesion expansion contributes to progression and increased disability, while remyelination can recover neurological deficits. However, mechanisms driving lesion dynamics are largely unclear, hindering the development of effective therapeutics. We propose that distinct states of microglia are involved in lesion expansion and remyelination 2,3. Using Stereo-seq, an RNA capture based high-resolution spatial transcriptomics technology with single-cell resolution, on post-mortem human brain tissue, we compared mixed active/inactive lesions with lipid-laden foamy microglia with lesions containing ramified microglia. We identified distinct cellular and molecular mechanisms underlying lesion activity and remyelination, linked to microglia phenotypes and states. Lesions with foamy microglia were characterized by elevated immune activation, increased lymphocyte densities, upregulated immunoglobulin production (IGHG1, IGHG3), increased complement system activity, indication of iron dysregulation (FTL, FTH1), and increased demyelination. In contrast, lesions with ramified microglia exhibited gene expression profiles indicative of myelin stability (ABCA2, QKI) and neuro-axonal protection, fostering an environment conducive to repair and remyelination. Our findings highlight the role of microglial states in lesion expansion and repair in MS and offer promising avenues for the development of therapeutic approaches aimed at preventing MS disability progression. Competing Interest Statement IH has advisory functions for Muna Therapeutics. Data availability Data will be publicly available at the website of the Human Protein Atlas. Raw data will be available upon reasonable request.