TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis

Francesca Cignarella, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA.
Fabia Filipello, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA.
Bryan Bollman, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA.
Claudia Cantoni, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA.Follow
Alberto Locca, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA.
Robert Mikesell, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA.
Melissa Manis, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA.
Adiljan Ibrahim, Alector, 131 Oyster Point Blvd #600, South San Francisco, CA, 94080, USA.
Li Deng, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA.
Bruno A. Benitez, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Carlos Cruchaga, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Danilo Licastro, ARGO Open Lab Platform for Genome sequencing, AREA Science Park, Padriciano 99, 34149, Trieste, Italy.
Kathie Mihindukulasuriya, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Oscar Harari, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Michael Buckland, Brain and Mind Centre, University of Sydney, 94 Mallett St Camperdown, Sydney, NSW, 2050, Australia.
David M. Holtzman, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA.
Arnon Rosenthal, Alector, 131 Oyster Point Blvd #600, South San Francisco, CA, 94080, USA.
Tina Schwabe, Alector, 131 Oyster Point Blvd #600, South San Francisco, CA, 94080, USA.
Ilaria Tassi, Alector, 131 Oyster Point Blvd #600, South San Francisco, CA, 94080, USA. Ilaria.tassi@alector.com.
Laura Piccio, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA. picciol@wustl.edu.

Document Type

Article

Abstract

Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS) triggered by autoimmune mechanisms. Microglia are critical for the clearance of myelin debris in areas of demyelination, a key step to allow remyelination. TREM2 is expressed by microglia and promotes microglial survival, proliferation, and phagocytic activity. Herein we demonstrate that TREM2 was highly expressed on myelin-laden phagocytes in active demyelinating lesions in the CNS of subjects with MS. In gene expression studies, macrophages from subjects with TREM2 genetic deficiency displayed a defect in phagocytic pathways. Treatment with a new TREM2 agonistic antibody promoted the clearance of myelin debris in the cuprizone model of CNS demyelination. Effects included enhancement of myelin uptake and degradation, resulting in accelerated myelin debris removal by microglia. Most importantly, antibody-dependent TREM2 activation on microglia increased density of oligodendrocyte precursors in areas of demyelination, as well as the formation of mature oligodendrocytes thus enhancing remyelination and axonal integrity. These results are relevant as they propose TREM2 on microglia as a potential new target to promote remyelination.

Medical Subject Headings

Adult; Aged; Animals; Disease Models, Animal; Female; Humans; Male; Membrane Glycoproteins (metabolism); Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia (metabolism); Middle Aged; Multiple Sclerosis (metabolism, pathology); Myelin Sheath (metabolism, pathology); Phagocytosis (physiology); Receptors, Immunologic (metabolism); Remyelination (physiology)

Publication Date

10-1-2020

Publication Title

Acta neuropathologica

E-ISSN

1432-0533

Volume

140

Issue

4

First Page

513

Last Page

534

PubMed ID

32772264

Digital Object Identifier (DOI)

10.1007/s00401-020-02193-z

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