Oligodendroglial TNFR2 mediates membrane TNF-dependent repair in experimental autoimmune encephalomyelitis by promoting oligodendrocyte differentiation and remyelination

Pernille M. Madsen, Dario Motti, Shaffiat Karmally, David E. Szymkowski, Kate Lykke Lambertsen, John R. Bethea, Roberta Brambilla

Research output: Contribution to journalArticle

30 Citations (Scopus)

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:TNFR2fl/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:TNFR2fl/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. TNFR2ablation 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.

Original languageEnglish (US)
Pages (from-to)5128-5143
Number of pages16
JournalJournal of Neuroscience
Volume36
Issue number18
DOIs
StatePublished - May 4 2016

Fingerprint

Autoimmune Experimental Encephalomyelitis
Tumor Necrosis Factor Receptors
Oligodendroglia
Membranes
Receptors, Tumor Necrosis Factor, Type I
Multiple Sclerosis
Myelin Sheath
Nervous System Diseases
MicroRNAs
Axons
Disease Progression
Cell Survival
Cell Proliferation
Pathology
Inflammation

Keywords

  • Cytokine
  • Demyelination
  • Multiple sclerosis
  • Neurodegeneration
  • Neuroinflammation
  • Remyelination

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Oligodendroglial TNFR2 mediates membrane TNF-dependent repair in experimental autoimmune encephalomyelitis by promoting oligodendrocyte differentiation and remyelination. / Madsen, Pernille M.; Motti, Dario; Karmally, Shaffiat; Szymkowski, David E.; Lambertsen, Kate Lykke; Bethea, John R.; Brambilla, Roberta.

In: Journal of Neuroscience, Vol. 36, No. 18, 04.05.2016, p. 5128-5143.

Research output: Contribution to journalArticle

Madsen, Pernille M. ; Motti, Dario ; Karmally, Shaffiat ; Szymkowski, David E. ; Lambertsen, Kate Lykke ; Bethea, John R. ; Brambilla, Roberta. / Oligodendroglial TNFR2 mediates membrane TNF-dependent repair in experimental autoimmune encephalomyelitis by promoting oligodendrocyte differentiation and remyelination. In: Journal of Neuroscience. 2016 ; Vol. 36, No. 18. pp. 5128-5143.
@article{7a5a6cb02d3a441db5023f0776bd01c6,
title = "Oligodendroglial TNFR2 mediates membrane TNF-dependent repair in experimental autoimmune encephalomyelitis by promoting oligodendrocyte differentiation and remyelination",
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:TNFR2fl/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:TNFR2fl/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. TNFR2ablation 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.",
keywords = "Cytokine, Demyelination, Multiple sclerosis, Neurodegeneration, Neuroinflammation, Remyelination",
author = "Madsen, {Pernille M.} and Dario Motti and Shaffiat Karmally and Szymkowski, {David E.} and Lambertsen, {Kate Lykke} and Bethea, {John R.} and Roberta Brambilla",
year = "2016",
month = "5",
day = "4",
doi = "10.1523/JNEUROSCI.0211-16.2016",
language = "English (US)",
volume = "36",
pages = "5128--5143",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "18",

}

TY - JOUR

T1 - Oligodendroglial TNFR2 mediates membrane TNF-dependent repair in experimental autoimmune encephalomyelitis by promoting oligodendrocyte differentiation and remyelination

AU - Madsen, Pernille M.

AU - Motti, Dario

AU - Karmally, Shaffiat

AU - Szymkowski, David E.

AU - Lambertsen, Kate Lykke

AU - Bethea, John R.

AU - Brambilla, Roberta

PY - 2016/5/4

Y1 - 2016/5/4

N2 - 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:TNFR2fl/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:TNFR2fl/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. TNFR2ablation 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.

AB - 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:TNFR2fl/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:TNFR2fl/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. TNFR2ablation 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.

KW - Cytokine

KW - Demyelination

KW - Multiple sclerosis

KW - Neurodegeneration

KW - Neuroinflammation

KW - Remyelination

UR - http://www.scopus.com/inward/record.url?scp=84965068941&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84965068941&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.0211-16.2016

DO - 10.1523/JNEUROSCI.0211-16.2016

M3 - Article

C2 - 27147664

AN - SCOPUS:84965068941

VL - 36

SP - 5128

EP - 5143

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 18

ER -