Microglia regulate cortical remyelination via ΤNFR1-dependent phenotypic polarization [scRNA-Seq]

Microglia are strongly implicated in demyelinating neurodegenerative diseases with increasing evidence for roles in protection and healing, but the mechanisms that control CNS remyelination are poorly understood. Here we show that microglia-specific deletion of TNFR1 and pharmacological inhibition of soluble TNF (solTNF) or downstream IL-1R allow maturation of highly activated disease-associated microglia with increased size and myelin phagocytosis capacity that accelerate cortical remyelination and motor recovery. Single cell transcriptomic analysis of cortex at disease onset reveal that solTNF inhibition enhances reparative IL-10-responsive, while preventing damaging IL-1-related signatures of disease-associated microglia. Longitudinal brain transcriptome analysis through disease reveal earlier recovery upon therapeutic loss of microglia TNFR1. Functional relevance of microglia inflammatory polarization pathways for disease is validated in vivo. Furthermore, disease-state microglia producing downstream IL-1/IL-18/NLRP3/CASP1 targets are identified in human demyelinating lesions. Overall, redirecting disease microglia polarization by targeting cytokines is a potential approach for improving CNS repair in demyelinating disorders.