Microglia regulate cortical remyelination via TNFR1-dependent phenotypic polarization

Athena Boutou; Ilias Roufagalas; Katerina Politopoulou; Spyros Tastsoglou; Maya Abouzeid; Giorgos Skoufos; Laia Verdu de Juan; Jeong Hun Ko; Vasiliki Kyrargyri; Artemis G Hatzigeorgiou; Christopher J Barnum; Raymond J Tesi; Jan Bauer; Hans Lassmann; Michael R Johnson; Lesley Probert

doi:10.1016/j.celrep.2024.114894

Microglia regulate cortical remyelination via TNFR1-dependent phenotypic polarization

Cell Rep. 2024 Oct 23;43(11):114894. doi: 10.1016/j.celrep.2024.114894. Online ahead of print.

Authors

Athena Boutou¹, Ilias Roufagalas¹, Katerina Politopoulou¹, Spyros Tastsoglou², Maya Abouzeid³, Giorgos Skoufos², Laia Verdu de Juan⁴, Jeong Hun Ko³, Vasiliki Kyrargyri¹, Artemis G Hatzigeorgiou², Christopher J Barnum⁵, Raymond J Tesi⁵, Jan Bauer⁴, Hans Lassmann⁴, Michael R Johnson³, Lesley Probert⁶

Affiliations

¹ Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, 11521 Athens, Greece.
² DIANA-Lab, Department of Computer Science and Biomedical Informatics, University of Thessaly, 35131 Lamia, Greece; Hellenic Pasteur Institute, 11521 Athens, Greece.
³ Department of Brain Sciences, Imperial College Faculty of Medicine, London W120NN, UK.
⁴ Center for Brain Research, Medical University of Vienna, Vienna 1090, Austria.
⁵ INmune Bio, Boca Raton, FL 33432, USA.
⁶ Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, 11521 Athens, Greece. Electronic address: lesley.probert@gmail.com.

PMID: 39446583
DOI: 10.1016/j.celrep.2024.114894

Abstract

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 tumor necrosis factor receptor 1 (TNFR1) and pharmacological inhibition of soluble TNF (solTNF) or downstream interleukin-1 receptor (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 reveals 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 reveals earlier recovery upon therapeutic loss of microglia TNFR1. The functional relevance of microglia inflammatory polarization pathways for disease is validated in vivo. Furthermore, disease-state microglia producing downstream IL-1/IL-18/caspase-11 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.

Keywords: CP: Immunology; CP: Neuroscience; DAM; IL-1; TNF; demyelination; microglia; multiple sclerosis; neuroinflammation; neuromyelitis optica; oligodendrocyte differentiation; remyelination.