TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis
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...
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| Veröffentlicht in: | Acta neuropathologica 2020-10, Vol.140 (4), p.513-534 |
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| creator | Cignarella, Francesca Filipello, Fabia Bollman, Bryan Cantoni, Claudia Locca, Alberto Mikesell, Robert Manis, Melissa Ibrahim, Adiljan Deng, Li Benitez, Bruno A. Cruchaga, Carlos Licastro, Danilo Mihindukulasuriya, Kathie Harari, Oscar Buckland, Michael Holtzman, David M. Rosenthal, Arnon Schwabe, Tina Tassi, Ilaria Piccio, Laura |
| description | 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. |
| doi_str_mv | 10.1007/s00401-020-02193-z |
| format | Article |
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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.</description><identifier>ISSN: 0001-6322</identifier><identifier>EISSN: 1432-0533</identifier><identifier>DOI: 10.1007/s00401-020-02193-z</identifier><identifier>PMID: 32772264</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Adult ; Aged ; Analysis ; Animals ; Antibodies ; Central nervous system ; Cuprizone ; Demyelination ; Disease Models, Animal ; Ethylenediaminetetraacetic acid ; Female ; Gene expression ; Glial stem cells ; Humans ; Macrophages ; Male ; Medicine ; Medicine & Public Health ; Membrane Glycoproteins - metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microglia ; Microglia - metabolism ; Middle Aged ; Multiple sclerosis ; Multiple Sclerosis - metabolism ; Multiple Sclerosis - pathology ; Myelin ; Myelin Sheath - metabolism ; Myelin Sheath - pathology ; Myelination ; Neurodegenerative diseases ; Neurosciences ; Oligodendrocytes ; Original Paper ; Pathology ; Phagocytes ; Phagocytosis - physiology ; Receptors, Immunologic - metabolism ; Remyelination - physiology ; Viral antibodies</subject><ispartof>Acta neuropathologica, 2020-10, Vol.140 (4), p.513-534</ispartof><rights>The Author(s) 2020</rights><rights>COPYRIGHT 2020 Springer</rights><rights>The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Acta neuropathologica</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cignarella, Francesca</au><au>Filipello, Fabia</au><au>Bollman, Bryan</au><au>Cantoni, Claudia</au><au>Locca, Alberto</au><au>Mikesell, Robert</au><au>Manis, Melissa</au><au>Ibrahim, Adiljan</au><au>Deng, Li</au><au>Benitez, Bruno A.</au><au>Cruchaga, Carlos</au><au>Licastro, Danilo</au><au>Mihindukulasuriya, Kathie</au><au>Harari, Oscar</au><au>Buckland, Michael</au><au>Holtzman, David M.</au><au>Rosenthal, Arnon</au><au>Schwabe, Tina</au><au>Tassi, Ilaria</au><au>Piccio, Laura</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis</atitle><jtitle>Acta neuropathologica</jtitle><stitle>Acta Neuropathol</stitle><addtitle>Acta Neuropathol</addtitle><date>2020-10-01</date><risdate>2020</risdate><volume>140</volume><issue>4</issue><spage>513</spage><epage>534</epage><pages>513-534</pages><issn>0001-6322</issn><eissn>1432-0533</eissn><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.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>32772264</pmid><doi>10.1007/s00401-020-02193-z</doi><tpages>22</tpages><orcidid>https://orcid.org/0000-0002-8760-109X</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Acta neuropathologica, 2020-10, Vol.140 (4), p.513-534 |
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| language | eng |
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| subjects | Adult Aged Analysis Animals Antibodies Central nervous system Cuprizone Demyelination Disease Models, Animal Ethylenediaminetetraacetic acid Female Gene expression Glial stem cells Humans Macrophages Male Medicine Medicine & Public Health Membrane Glycoproteins - metabolism Mice Mice, Inbred C57BL Mice, Knockout Microglia Microglia - metabolism Middle Aged Multiple sclerosis Multiple Sclerosis - metabolism Multiple Sclerosis - pathology Myelin Myelin Sheath - metabolism Myelin Sheath - pathology Myelination Neurodegenerative diseases Neurosciences Oligodendrocytes Original Paper Pathology Phagocytes Phagocytosis - physiology Receptors, Immunologic - metabolism Remyelination - physiology Viral antibodies |
| title | TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis |
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