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 G. Ellman, Robert W. Keane, Bettina H. Clausen, Kate L. Lambertsen, Roberta Brambilla

Research output: Contribution to journalArticle

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 (US)
JournalBrain, Behavior, and Immunity
DOIs
StateAccepted/In press - Jan 1 2019

Keywords

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

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience

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    Madsen, P. M., Desu, H. L., Vaccari, J. P. D. R., Florimon, Y., Ellman, D. G., Keane, R. W., Clausen, B. H., Lambertsen, K. L., & Brambilla, R. (Accepted/In press). Oligodendrocytes modulate the immune-inflammatory response in EAE via TNFR2 signaling. Brain, Behavior, and Immunity. https://doi.org/10.1016/j.bbi.2019.11.017