TY - JOUR
T1 - TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis
AU - Cignarella, Francesca
AU - Filipello, Fabia
AU - Bollman, Bryan
AU - Cantoni, Claudia
AU - Locca, Alberto
AU - Mikesell, Robert
AU - Manis, Melissa
AU - Ibrahim, Adiljan
AU - Deng, Li
AU - Benitez, Bruno A.
AU - Cruchaga, Carlos
AU - Licastro, Danilo
AU - Mihindukulasuriya, Kathie
AU - Harari, Oscar
AU - Buckland, Michael
AU - Holtzman, David M.
AU - Rosenthal, Arnon
AU - Schwabe, Tina
AU - Tassi, Ilaria
AU - Piccio, Laura
N1 - Funding Information:
We are thankful to NHD patients and their families for kindly providing peripheral blood samples for the analyses included in this manuscript. We thank R. C. Paolicelli for her valuable advice with Imaris analysis. This study was supported by grant # RF1AG058501 (to L.P. and C. Cruchaga) from the National Institute of Aging. Funding for this study was also provided by Alector, Fondazione Italiana Sclerosi Multipla (FISM; 2017/R/20) and co-financed with the ‘5 per mille’ public funding, and The Trish MS Research Foundation. C. Cantoni was supported during the course of this study by the National MS Society Career Transition Fellowship (TA-1805-31003). F.F was supported by a McDonnell Center for Cellular and Molecular Neurobiology (Washington University in St Louis) postdoctoral fellowship and she is the recipient of a 2018-0364-CARIPLO grant. Funding for this project was provided by the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital. Experiments/data/analysis/presentation [by the use of a Zeiss LSM880 Airyscan confocal microscope, an Olympus FV1200 confocal microscope, and Imaris Software (Bitplane, Switzerland)] were performed in part through the use of Washington University Center for Cellular Imaging (WUCCI) supported by Washington University School of Medicine, The Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (CDI-CORE-2015-505 and CDI-CORE-2019-813) and the Foundation for Barnes-Jewish Hospital (3770 and 4642). Confocal/super-resolution data were generated on a Zeiss LSM 880 Airyscan Confocal Microscope which was purchased with support from the Office of Research Infrastructure Programs (ORIP), a part of the NIH Office of the Director under grant OD021629.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85089154392&partnerID=8YFLogxK
U2 - 10.1007/s00401-020-02193-z
DO - 10.1007/s00401-020-02193-z
M3 - Article
C2 - 32772264
AN - SCOPUS:85089154392
SN - 0001-6322
VL - 140
SP - 513
EP - 534
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 4
ER -