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

Francesca Cignarella,David M Holtzman,Adiljan Ibrahim,Bryan Bollman,Carlos Cruchaga,Arnon Rosenthal,Claudia Cantoni,Robert Mikesell,Danilo Licastro,Michael E Buckland ,Bruno A Benitez,Oscar Harari,Alberto Locca,Li Deng,Fabia Filipello,Tina Schwabe,Ilaria Tassi,Kathie A Mihindukulasuriya ,Melissa Manis,Laura Piccio

doi:10.1007/s00401-020-02193-z

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.

Highlights

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS), whose pathogenesis involves inflammatory and neurodegenerative processes
The general consensus is that triggering receptor expressed on myeloid cells-2 (TREM2) is expressed by microglia in the CNS, especially after activation [6, 21, 47]
TREM2 expression was reported in active demyelinating lesions on myelin-laden macrophages, which are clearing out myelin debris, a critical a

Summary

Introduction

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS), whose pathogenesis involves inflammatory and neurodegenerative processes. Efficient myelin debris removal and clearance by phagocytic cells are critical to eliminate inhibitory signals interfering with OPC activation, recruitment to the site of demyelination and/or differentiation into myelinating mature OLs [14, 26, 27]. Microglial cells and infiltrating monocytes/macrophages can have a dual role in MS lesions They could contribute to myelin damage and lesion expansion, or they may have a protective role by clearing myelin debris, reducing inflammation and secreting regenerative factors promoting remyelination [48]. TREM2 is a phospholipid sensing receptor known to sustain microglial cell activation and expansion in response to demyelination or amyloid plaques in Alzheimer’s disease (AD) [8, 42, 50]. TREM2 was proposed to be a key transcriptional regulator of cholesterol metabolism during chronic phagocytic activity for myelin clearance in response to demyelination [35]

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Results

Conclusion