The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index.
TNFα promotes proliferation of oligodendrocyte progenitors and remyelination
Abstract
Here we used mice lacking tumor necrosis factor-alpha (TNF alpha) and its associated receptors to study a model of demyelination and remyelination in which these events could be carefully controlled using a toxin, cuprizone. Unexpectedly, the lack of TNF alpha led to a significant delay in remyelination as assessed by histology, immunohistochemistry for myelin proteins and electron microscopy coupled with morphometric analysis. Failure of repair correlated with a reduction in the pool of proliferating oligodendrocyte progenitors (bromodeoxyuridine-labeled NG2(+) cells) followed by a reduction in the number of mature oligodendrocytes. Analysis of mice lacking TNF receptor 1 (TNFR1) or TNFR2 indicated that TNFR2, not TNFR1, is critical to oligodendrocyte regeneration. This unexpected reparative role for TNF alpha in the CNS is important for understanding oligodendrocyte regeneration/proliferation, nerve remyelination and the design of new therapeutics for demyelinating diseases.
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In the citing paper
“This aligns with the notion that the debris-clearing function of myeloid cells and mediators released from innate immune cells stimulate remyelination.61-63”
From BCAS1-positive oligodendrocytes enable efficient cortical remyelination in multiple sclerosis (2025) · cites this paper as [61]
In the citing paper
“We found SJL mice demyelinate partially at midline (Figure 2A), whereas C57BL/6 mice show robust demyelination, particularly at week 5 2, 23, 35.”
From SJL Mice Exposed to Cuprizone Intoxication Reveal Strain and Gender Pattern Differences in Demyelination (2009) · cites this paper as [2]
In the citing paper
“C57BL/6 mice showed greater than 50% remyelination within 2 weeks of discontinuation of cuprizone 2, 42, which is in stark contrast to the reduced remyelination reported here for SJL.”
From SJL Mice Exposed to Cuprizone Intoxication Reveal Strain and Gender Pattern Differences in Demyelination (2009) · cites this paper as [2]
In the citing paper
“The increased severity in EAE may be because of T‐cell immune mechanisms that are not induced by cuprizone intoxication 2, 24.”
From SJL Mice Exposed to Cuprizone Intoxication Reveal Strain and Gender Pattern Differences in Demyelination (2009) · cites this paper as [2]
In the citing paper
“Thus, unlike microglia and astrocytes in C57BL/6 mice that respond vigorously to demyelination 2, 23, 39, these cell types in SJL mice have a guarded response at midline and in the lateral region, which correlates with subdued demyelination.”
From SJL Mice Exposed to Cuprizone Intoxication Reveal Strain and Gender Pattern Differences in Demyelination (2009) · cites this paper as [2]
In the citing paper
“TNF expression levels are increased after one week of cuprizone-induced demyelination in vivo [224] and TNFα−/− mice showed a delay in demyelination in the cuprizone model [56], consistent with a role for TNF to exacerbate cuprizone-induced demyelination.”
From Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination (2022) · cites this paper as [224]
In the citing paper
“However, TNF is also required for remyelination [224].”
From Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination (2022) · cites this paper as [224]
In the citing paper
“Overall, cuprizone-induced de- and remyelination are not mediated by B or T cells, as shown by the use of RAG −/− mice that lack lymphocytes (Arnett et al., 2001; Hiremath et al., 2008).”
From Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned (2014) · cites this paper as Arnett et al., 2001
In the citing paper
“In the cuprizone model, TNF-α was demonstrated to act as well in a bivalent manner since TNF-α −/− mice displayed a reduced loss of oligodendrocytes during the first 3.5 weeks of cuprizone feeding but also a significantly diminished ability to remyelinate (Arnett et al., 2001).”
From Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned (2014) · cites this paper as Arnett et al., 2001
In the citing paper
“Furthermore, similar to TNF-α-deficient mice TNFR2 −/− mice displayed diminished/delayed regeneration of myelin”
From Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned (2014) · cites this paper as Arnett et al., 2001
In the citing paper
“In this study TNFR2 but not TNFR1 has been shown to be gradually up-regulated during de- and remyelination (Arnett et al., 2001).”
From Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned (2014) · cites this paper as Arnett et al., 2001
In the citing paper
“However, a growing body of evidence corroborates the assumption that an adequate and controlled inflammatory response is required for a successful myelin regeneration promoting the clearance of myelin debris and stimulating proliferation/regeneration of myelin-forming oligodendrocytes (Diemel et al., 1998; Robinson and Miller, 1999; Arnett et al., 2001; Kotter et al., 2001, 2005, 2006; Setzu et al”
From Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned (2014) · cites this paper as Arnett et al., 2001
In the citing paper
“suggesting that beneficial effects of TNF-α on proliferation of OPC and subsequent remyelination are promoted through the TNFR2 pathway (Arnett et al., 2001).”
From Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned (2014) · cites this paper as Arnett et al., 2001
In the citing paper
“Functional studies using recombinase activating gene-1 knockout (RAG-1 -/-) mice suggest that the recruited CD3 + lymphocytes do not play a major role during cuprizone-induced demyelination and the subsequent endogenous remyelination process (Arnett et al., 2001;Bieber et al., 2003;Hiremath et al., 2008).”
From Cuprizone‐induced demyelination triggers a CD8‐pronounced T cell recruitment (2021) · cites this paper as Arnett et al., 2001
In the citing paper
“Such cytokines can thus be harmful for the cerebral elements (138) but they also play beneficial roles in the inflammatory response (161–163).”
From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [161]
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Metadata
- Authors
- Arnett, H. A., Mason, J., Marino, M., Suzuki, K., Matsushima, G. K., & Ting, J. P.-Y.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Ting, Jenny P.-Y.
- Venue
- Nature Neuroscience
- Published
- 2001-10-15
- Volume
- 4
- Issue
- 11
- Pages
- 1116-1122
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W1509596990
- Cited by
- 1,012
- References
- 48
- Citations by year
- 2026: 26 · 2025: 30 · 2024: 37 · 2023: 39 · 2022: 40 · 2021: 43 · 2020: 46 · 2019: 43 · 2018: 34 · 2017: 40 · 2016: 36 · 2015: 45 · 2014: 46 · 2013: 45 · 2012: 51
- FWCI
- 7.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS34190, R01NS034190)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- TNF-α, remyelination, demyelination, oligodendrocyte progenitors, oligodendrocyte proliferation, TNF receptor 1, TNF receptor 2, cuprizone, oligodendrocyte precursor cells, demyelinating disease, central nervous system regeneration
- MeSH terms
- Animals, B-Lymphocytes, Brain Chemistry, Corpus Callosum, Cuprizone, Demyelinating Diseases, Disease Models, Animal, Humans, Immunohistochemistry, Macrophages, Male, Monoamine Oxidase Inhibitors, Myelin Sheath, Oligodendroglia, Stem Cells, Tumor Necrosis Factor-alpha, Antigens, CD, Up-Regulation, Apoptosis, Microglia, Receptors, Tumor Necrosis Factor, Mice, Knockout, In Situ Nick-End Labeling, Receptors, Tumor Necrosis Factor, Type I, Receptors, Tumor Necrosis Factor, Type II, Mice
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