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
Affiliations
Athena Boutou
Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, 11521 Athens, Greece
Ilias Roufagalas
Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, 11521 Athens, Greece
Katerina Politopoulou
Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, 11521 Athens, Greece
Spyros Tastsoglou
DIANA-Lab, Department of Computer Science and Biomedical Informatics, University of Thessaly, 35131 Lamia, Greece; Hellenic Pasteur Institute, 11521 Athens, Greece
Maya Abouzeid
Department of Brain Sciences, Imperial College Faculty of Medicine, London W120NN, UK
Giorgos Skoufos
DIANA-Lab, Department of Computer Science and Biomedical Informatics, University of Thessaly, 35131 Lamia, Greece; Hellenic Pasteur Institute, 11521 Athens, Greece
Laia Verdu de Juan
Center for Brain Research, Medical University of Vienna, Vienna 1090, Austria
Jeong Hun Ko
Department of Brain Sciences, Imperial College Faculty of Medicine, London W120NN, UK
Vasiliki Kyrargyri
Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, 11521 Athens, Greece
Artemis G. Hatzigeorgiou
DIANA-Lab, Department of Computer Science and Biomedical Informatics, University of Thessaly, 35131 Lamia, Greece; Hellenic Pasteur Institute, 11521 Athens, Greece
Christopher J. Barnum
INmune Bio, Boca Raton, FL 33432, USA
Raymond J. Tesi
INmune Bio, Boca Raton, FL 33432, USA
Jan Bauer
Center for Brain Research, Medical University of Vienna, Vienna 1090, Austria
Hans Lassmann
Center for Brain Research, Medical University of Vienna, Vienna 1090, Austria
Michael R. Johnson
Department of Brain Sciences, Imperial College Faculty of Medicine, London W120NN, UK
Lesley Probert
Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, 11521 Athens, Greece; Corresponding author
Summary: 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.
