Oligodendrocytes modulate the immune-inflammatory response in EAE via TNFR2 signaling

Pernille M. Madsen, Haritha L. Desu, Juan Pablo de Rivero Vaccari, Yoleinny Florimon, Ditte Gry Ellman, Robert W. Keane, Bettina Hjelm Clausen, Kate Lykke Lambertsen, Roberta Brambilla

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

The pleotropic cytokine tumor necrosis factor (TNF) is involved in the pathophysiology of multiple sclerosis (MS). In various models of MS, including experimental autoimmune encephalomyelitis (EAE), the membrane-bound form of TNF (tmTNF), which signals primarily via TNFR2, mediates protective and reparative effects, whereas the soluble form (solTNF), which signals primarily via TNFR1, promotes pro-inflammatory and detrimental functions. In this study, we investigated the role of TNFR2 expressed in oligodendrocytes in the early phase of EAE pathogenesis. We demonstrated that mice with specific ablation of oligodendroglial TNFR2 displayed early onset and higher peak of motor dysfunction when subjected to EAE, in advance of which accelerated infiltration of immune cells was observed as early as 10 days post EAE induction. The immune cell influx was preceded by microglial activation and increased blood brain barrier permeability. Lack of oligodendroglial TNFR2 accelerated the expression of inflammatory cytokines as well as expression and activation of the inflammasome. Gene expression profiling of oligodendrocytes sorted from the spinal cord 14 days post EAE induction showed robust upregulation of inflammatory genes, some of which were elevated in cells lacking TNFR2 compared to controls. Together, our data demonstrate that oligodendrocytes are directly involved in inflammation and immune modulation in CNS disease and this function is regulated, at least in part, by TNFR2.

Original languageEnglish
JournalBrain, Behavior, and Immunity
Volume84
Pages (from-to)132-146
ISSN0889-1591
DOIs
Publication statusPublished - Feb 2020

Fingerprint

Receptors, Tumor Necrosis Factor, Type II
Autoimmune Experimental Encephalomyelitis
Oligodendroglia
Receptors, Tumor Necrosis Factor, Type I
Membranes
Central Nervous System Diseases
Gene Expression Profiling
Up-Regulation
Tumor Necrosis Factor-alpha

Keywords

  • Cytokines
  • Demyelination
  • Multiple sclerosis
  • Neurodegeneration
  • Neuroinflammation
  • Oligodendrocytes
  • Tumor necrosis factor

Cite this

Madsen, P. M., Desu, H. L., Pablo de Rivero Vaccari, J., Florimon, Y., Ellman, D. G., Keane, R. W., ... Brambilla, R. (2020). Oligodendrocytes modulate the immune-inflammatory response in EAE via TNFR2 signaling. Brain, Behavior, and Immunity, 84, 132-146. https://doi.org/10.1016/j.bbi.2019.11.017
Madsen, Pernille M. ; Desu, Haritha L. ; Pablo de Rivero Vaccari, Juan ; Florimon, Yoleinny ; Ellman, Ditte Gry ; Keane, Robert W. ; Clausen, Bettina Hjelm ; Lambertsen, Kate Lykke ; Brambilla, Roberta. / Oligodendrocytes modulate the immune-inflammatory response in EAE via TNFR2 signaling. In: Brain, Behavior, and Immunity. 2020 ; Vol. 84. pp. 132-146.
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abstract = "The pleotropic cytokine tumor necrosis factor (TNF) is involved in the pathophysiology of multiple sclerosis (MS). In various models of MS, including experimental autoimmune encephalomyelitis (EAE), the membrane-bound form of TNF (tmTNF), which signals primarily via TNFR2, mediates protective and reparative effects, whereas the soluble form (solTNF), which signals primarily via TNFR1, promotes pro-inflammatory and detrimental functions. In this study, we investigated the role of TNFR2 expressed in oligodendrocytes in the early phase of EAE pathogenesis. We demonstrated that mice with specific ablation of oligodendroglial TNFR2 displayed early onset and higher peak of motor dysfunction when subjected to EAE, in advance of which accelerated infiltration of immune cells was observed as early as 10 days post EAE induction. The immune cell influx was preceded by microglial activation and increased blood brain barrier permeability. Lack of oligodendroglial TNFR2 accelerated the expression of inflammatory cytokines as well as expression and activation of the inflammasome. Gene expression profiling of oligodendrocytes sorted from the spinal cord 14 days post EAE induction showed robust upregulation of inflammatory genes, some of which were elevated in cells lacking TNFR2 compared to controls. Together, our data demonstrate that oligodendrocytes are directly involved in inflammation and immune modulation in CNS disease and this function is regulated, at least in part, by TNFR2.",
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author = "Madsen, {Pernille M.} and Desu, {Haritha L.} and {Pablo de Rivero Vaccari}, Juan and Yoleinny Florimon and Ellman, {Ditte Gry} and Keane, {Robert W.} and Clausen, {Bettina Hjelm} and Lambertsen, {Kate Lykke} and Roberta Brambilla",
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Oligodendrocytes modulate the immune-inflammatory response in EAE via TNFR2 signaling. / Madsen, Pernille M.; Desu, Haritha L.; Pablo de Rivero Vaccari, Juan ; Florimon, Yoleinny; Ellman, Ditte Gry; Keane, Robert W. ; Clausen, Bettina Hjelm; Lambertsen, Kate Lykke; Brambilla, Roberta.

In: Brain, Behavior, and Immunity, Vol. 84, 02.2020, p. 132-146.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Oligodendrocytes modulate the immune-inflammatory response in EAE via TNFR2 signaling

AU - Madsen, Pernille M.

AU - Desu, Haritha L.

AU - Pablo de Rivero Vaccari, Juan

AU - Florimon, Yoleinny

AU - Ellman, Ditte Gry

AU - Keane, Robert W.

AU - Clausen, Bettina Hjelm

AU - Lambertsen, Kate Lykke

AU - Brambilla, Roberta

PY - 2020/2

Y1 - 2020/2

N2 - The pleotropic cytokine tumor necrosis factor (TNF) is involved in the pathophysiology of multiple sclerosis (MS). In various models of MS, including experimental autoimmune encephalomyelitis (EAE), the membrane-bound form of TNF (tmTNF), which signals primarily via TNFR2, mediates protective and reparative effects, whereas the soluble form (solTNF), which signals primarily via TNFR1, promotes pro-inflammatory and detrimental functions. In this study, we investigated the role of TNFR2 expressed in oligodendrocytes in the early phase of EAE pathogenesis. We demonstrated that mice with specific ablation of oligodendroglial TNFR2 displayed early onset and higher peak of motor dysfunction when subjected to EAE, in advance of which accelerated infiltration of immune cells was observed as early as 10 days post EAE induction. The immune cell influx was preceded by microglial activation and increased blood brain barrier permeability. Lack of oligodendroglial TNFR2 accelerated the expression of inflammatory cytokines as well as expression and activation of the inflammasome. Gene expression profiling of oligodendrocytes sorted from the spinal cord 14 days post EAE induction showed robust upregulation of inflammatory genes, some of which were elevated in cells lacking TNFR2 compared to controls. Together, our data demonstrate that oligodendrocytes are directly involved in inflammation and immune modulation in CNS disease and this function is regulated, at least in part, by TNFR2.

AB - The pleotropic cytokine tumor necrosis factor (TNF) is involved in the pathophysiology of multiple sclerosis (MS). In various models of MS, including experimental autoimmune encephalomyelitis (EAE), the membrane-bound form of TNF (tmTNF), which signals primarily via TNFR2, mediates protective and reparative effects, whereas the soluble form (solTNF), which signals primarily via TNFR1, promotes pro-inflammatory and detrimental functions. In this study, we investigated the role of TNFR2 expressed in oligodendrocytes in the early phase of EAE pathogenesis. We demonstrated that mice with specific ablation of oligodendroglial TNFR2 displayed early onset and higher peak of motor dysfunction when subjected to EAE, in advance of which accelerated infiltration of immune cells was observed as early as 10 days post EAE induction. The immune cell influx was preceded by microglial activation and increased blood brain barrier permeability. Lack of oligodendroglial TNFR2 accelerated the expression of inflammatory cytokines as well as expression and activation of the inflammasome. Gene expression profiling of oligodendrocytes sorted from the spinal cord 14 days post EAE induction showed robust upregulation of inflammatory genes, some of which were elevated in cells lacking TNFR2 compared to controls. Together, our data demonstrate that oligodendrocytes are directly involved in inflammation and immune modulation in CNS disease and this function is regulated, at least in part, by TNFR2.

KW - Cytokines

KW - Demyelination

KW - Multiple sclerosis

KW - Neurodegeneration

KW - Neuroinflammation

KW - Oligodendrocytes

KW - Tumor necrosis factor

U2 - 10.1016/j.bbi.2019.11.017

DO - 10.1016/j.bbi.2019.11.017

M3 - Journal article

C2 - 31785393

VL - 84

SP - 132

EP - 146

JO - Brain, Behavior, and Immunity

JF - Brain, Behavior, and Immunity

SN - 0889-1591

ER -

Madsen PM, Desu HL, Pablo de Rivero Vaccari J, Florimon Y, Ellman DG, Keane RW et al. Oligodendrocytes modulate the immune-inflammatory response in EAE via TNFR2 signaling. Brain, Behavior, and Immunity. 2020 Feb;84:132-146. https://doi.org/10.1016/j.bbi.2019.11.017