Oligodendroglial TNFR2 mediates membrane TNF-dependent repair in experimental autoimmune encephalomyelitis by promoting oligodendrocyte differentiation and remyelination
Open accessAbstract
Tumor necrosis 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. SIGNIFICANCE STATEMENT Our study, using novel TNF receptor 2 (TNFR2) conditional KO mice with selective TNFR2 ablation in oligodendrocytes, provides the first direct evidence that TNFR2 is an important signal for oligodendrocyte differentiation. Following activation by transmembrane TNF, TNFR2 initiates pathways that drive oligodendrocytes into a reparative mode contributing to remyelination following disease. This identifies TNFR2 as a new molecular target for the development of therapeutic agents in multiple sclerosis.
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The differentiation of local oligodendrocyte progenitor cells into actively myelinating oligodendrocytes is stimulated by innate immune cells.
“Recent data have indicated that the differentiation of local oligodendrocyte progenitor cells into actively myelinating oligodendrocytes is stimulated by innate immune cells.64-67”
From BCAS1-positive oligodendrocytes enable efficient cortical remyelination in multiple sclerosis (2025) · cites this paper as [65]
The Discussion reports that TNFR2 activation in oligodendrocyte progenitor cells promotes their differentiation and sustains remyelination; the Results section also finds impaired differentiation when TNFR2 is absent. However, the cited passages do not establish that innate immune cells provide the stimulus, and the paper’s purified progenitor-cell cultures contained no microglia. Page numbers were not available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredTNFα activity is elevated in MS lesions, and blockade of soluble TNF improves outcomes in EAE.
“TNFα activity is elevated in MS lesions, and blockade of soluble TNF improves outcomes in EAE, supporting a potentially detrimental role of excessive TNF signaling during inflammatory demyelination52.”
From A comparative transcriptomic analysis of mouse demyelination models and multiple sclerosis lesions (2026) · cites this paper as [52]
Excessive TNF signaling during inflammatory demyelination is potentially detrimental.
“TNFα activity is elevated in MS lesions, and blockade of soluble TNF improves outcomes in EAE, supporting a potentially detrimental role of excessive TNF signaling during inflammatory demyelination52.”
From A comparative transcriptomic analysis of mouse demyelination models and multiple sclerosis lesions (2026) · cites this paper as [52]
The Cnp Cre driver line recombines floxed genes to virtually 100% in oligodendrocytes and up to 60% of OPCs.
“that recombines floxed genes to virtually 100% in oligodendrocytes and up to 60% of OPCs (Madsen et al., 2016;Saab et al., 2016;Vajda et al., 2015).”
From Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons (2024) · cites this paper as Madsen et al., 2016
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TNFα promotes proliferation of oligodendrocyte progenitors and remyelination
Arnett, H. A., Mason, J., Marino, M., Suzuki, K., Matsushima, G. K., & Ting, J. P.-Y. (2001) · Nature Neuroscience · doi:10.1038/nn738 · Cited by 1,012 · see citing works
Identification of Dynamically Regulated MicroRNA and mRNA Networks in Developing Oligodendrocytes
Lau, P., Verrier, J. D., Nielsen, J. A., Johnson, K. R., Notterpek, L., & Hudson, L. D. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.1932-08.2008 · Cited by 252 · see citing works
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“TNF α activity is elevated in MS lesions, and blockade of soluble TNF improves outcomes in EAE, supporting a potentially detrimental role of excessive TNF signaling during in fl ammatory demyelination 52 .”
- Authors
- Madsen, P. M., Motti, D., Karmally, S., Szymkowski, D. E., Lambertsen, K. L., Bethea, J. R., & Brambilla, R.
- Affiliations
- University of Miami (US)
- Nationwide Children's Hospital (US)
- Xencor (United States) (US)
- University of Southern Denmark (DK)
- Drexel University (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2016-05-04
- Volume
- 36
- Issue
- 18
- Pages
- 5128-5143
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4854972
- OpenAlex
- W2325615207
- Cited by
- 161
- References
- 3
- Citations by year
- 2026: 15 · 2025: 12 · 2024: 17 · 2023: 23 · 2022: 14 · 2021: 17 · 2020: 17 · 2019: 20 · 2018: 11 · 2017: 10 · 2016: 4
- FWCI
- 13.63
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, other-oa)
- Funders
- Scleroseforeningen
- National Institute of Neurological Disorders and Stroke (R21NS084303, R01NS051709)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- TNF receptor 2, transmembrane TNF, oligodendrocyte differentiation, remyelination, experimental autoimmune encephalomyelitis, multiple sclerosis, oligodendrocyte precursor cells, microRNA, XPro1595, TNF receptor 1, neuroinflammation, conditional knockout
- MeSH terms
- Animals, Axons, Behavior, Animal, Cell Differentiation, Cell Survival, Encephalomyelitis, Autoimmune, Experimental, Female, Gene Expression Regulation, Male, Myelin Sheath, Nerve Regeneration, Neuroglia, Tumor Necrosis Factor-alpha, Mice, Knockout, Receptors, Tumor Necrosis Factor, Type II, Mice, Neural Stem Cells
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