Journal article
Oligodendroglial TNFR2 Mediates Membrane TNF-Dependent Repair in Experimental Autoimmune Encephalomyelitis by Promoting Oligodendrocyte Differentiation and Remyelination
The Journal of neuroscience, v 36(18), pp 5128-5143
04 May 2016
PMID: 27147664
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Tumornecrosis factor (TNF) is associated with the pathophysiology of various neurological disorders, including multiple sclerosis. It exists as a transmembrane form tmTNF, signaling via TNF receptor 2 (TNFR2) and TNFR1, and a soluble form, solTNF, signaling via TNFR1. Multiple sclerosis is associated with the detrimental effects of solTNF acting through TNFR1, while tmTNF promotes repair and remyelination. Here we demonstrate that oligodendroglial TNFR2 is a key mediator of tmTNF-dependent protection in experimental autoimmune encephalomyelitis (EAE). CNP-cre: TNFR2(fl/fl) mice with TNFR2 ablation in oligodendrocytes show exacerbation of the disease with increased axon and myelin pathology, reduced remyelination, and increased loss of oligodendrocyte precursor cells and mature oligodendrocytes. The clinical course of EAE is not improved by the solTNF inhibitor XPro1595 in CNP-cre: TNFR2(fl/fl) mice, indicating that for tmTNF to promote recovery TNFR2 in oligodendrocytes is required. We show that TNFR2 drives differentiation of oligodendrocyte precursor cells, but not proliferation or survival. TNFR2 ablation leads to dysregulated expression of microRNAs, among which are regulators of oligodendrocyte differentiation and inflammation, including miR-7a. Our data provide the first direct in vivo evidence that TNFR2 in oligodendrocytes is important for oligodendrocyte differentiation, thereby sustaining tmTNF-dependent repair in neuroimmune disease. Our studies identify TNFR2 in the CNS as a molecular target for the development of remyelinating agents, addressing the most pressing need in multiple sclerosis therapy nowadays.
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Details
- Title
- Oligodendroglial TNFR2 Mediates Membrane TNF-Dependent Repair in Experimental Autoimmune Encephalomyelitis by Promoting Oligodendrocyte Differentiation and Remyelination
- Creators
- Pernille M. Madsen - Miami Project to Cure ParalysisDario Motti - Nationwide Children's HospitalShaffiat Karmally - Miami Project to Cure ParalysisDavid E. Szymkowski - 4Xencor Inc., Monrovia, California 91016, andKate Lykke Lambertsen - University of Southern DenmarkJohn R. Bethea - Drexel UniversityRoberta Brambilla - Miami Project to Cure Paralysis
- Publication Details
- The Journal of neuroscience, v 36(18), pp 5128-5143
- Publisher
- Soc Neuroscience
- Number of pages
- 16
- Grant note
- R01NS051709 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) Miami Project To Cure Paralysis Fonden for Neurologisk Forskning 2012/R/2 / FISM (Fondazione Italiana Sclerosi Multipla); Fondazione Italiana Sclerosi Multipla (FISM) NS-084303-01A1 / National Institutes of Health/National Institute of Neurological Disorders and Stroke Grant R431-A29647-B20593 / Danish Multiple Sclerosis Society Fonden til Laegevidenskabens Fremme
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology
- Web of Science ID
- WOS:000378276600020
- Scopus ID
- 2-s2.0-84965068941
- Other Identifier
- 991019168314004721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Neurosciences