TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis.
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
Myelin Sheath
/ metabolism
Phagocytosis
/ physiology
Receptors, Immunologic
/ metabolism
Remyelination
/ physiology
Journal
Acta neuropathologica
ISSN: 1432-0533
Titre abrégé: Acta Neuropathol
Pays: Germany
ID NLM: 0412041
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
14
03
2020
accepted:
06
07
2020
revised:
01
07
2020
pubmed:
11
8
2020
medline:
1
6
2021
entrez:
11
8
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32772264
doi: 10.1007/s00401-020-02193-z
pii: 10.1007/s00401-020-02193-z
pmc: PMC7498497
doi:
Substances chimiques
Membrane Glycoproteins
0
Receptors, Immunologic
0
TREM2 protein, human
0
Trem2 protein, mouse
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
513-534Subventions
Organisme : NIA NIH HHS
ID : R01 AG057777
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG052411
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG003991
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG058501
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG044546
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG058922
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG044546
Pays : United States
Commentaires et corrections
Type : CommentIn
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