TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis
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ORIGINAL PAPER
TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis Francesca Cignarella1,10 · Fabia Filipello1,2 · Bryan Bollman1 · Claudia Cantoni1 · Alberto Locca1 · Robert Mikesell1 · Melissa Manis1 · Adiljan Ibrahim3 · Li Deng1,4 · Bruno A. Benitez5,6,7 · Carlos Cruchaga5,6,7 · Danilo Licastro8 · Kathie Mihindukulasuriya5,7 · Oscar Harari5,6,7 · Michael Buckland9 · David M. Holtzman1,6 · Arnon Rosenthal3 · Tina Schwabe3 · Ilaria Tassi3 · Laura Piccio1,7,9 Received: 14 March 2020 / Revised: 1 July 2020 / Accepted: 6 July 2020 © The Author(s) 2020
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.
Introduction
Francesca Cignarella and Fabia Filipello contributed equally. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00401-020-02193-z) contains supplementary material, which is available to authorized users.
Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS), whose pathogenesis involves inflammatory and neurodegenerative processes. Current MS immunomodulatory treatments target CNS inflammation, while therapies capable of regenerating
* Ilaria Tassi [email protected]
5
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA
* Laura Piccio [email protected]; [email protected]
6
Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA
7
NeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, MO 63110, USA
8
ARGO Open Lab Platform for Genome sequencing, AREA Science Park, Padriciano 99, 34149 Trieste, Italy
9
Brain and Mind Centre, University of Sydney, 94 Mallett St Camperdown, Sydney, NSW 2050
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