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

Acta Neuropathol. 2020 Oct;140(4):513-534. doi: 10.1007/s00401-020-02193-z. Epub 2020 Aug 9.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Multiple Sclerosis / pathology
  • Myelin Sheath / metabolism
  • Myelin Sheath / pathology*
  • Phagocytosis / physiology
  • Receptors, Immunologic / metabolism*
  • Remyelination / physiology*

Substances

  • Membrane Glycoproteins
  • Receptors, Immunologic
  • TREM2 protein, human
  • Trem2 protein, mouse