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Cell Rep. 2017 Jan 3;18(1):198-212. doi: 10.1016/j.celrep.2016.11.083.

Opposing Functions of Microglial and Macrophagic TNFR2 in the Pathogenesis of Experimental Autoimmune Encephalomyelitis.

Author information

  • 1The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
  • 2The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Center for Computational Science, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
  • 3Columbia University, New York, NY 10027, USA.
  • 4The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
  • 5The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C 5000, Denmark.
  • 6Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C 5000, Denmark.
  • 7The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Center for Computational Science, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Cellular and Molecular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
  • 8Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C 5000, Denmark; Brain Research - Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense C 5000, Denmark; Department of Neurology, Odense University Hospital, Odense C 5000, Denmark.
  • 9The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address: r.brambilla@miami.edu.

Abstract

In multiple sclerosis (MS), soluble tumor necrosis factor (TNF) is detrimental via activation of TNF receptor 1 (TNFR1), whereas transmembrane TNF is beneficial primarily by activating TNF receptor 2 (TNFR2). Here, we investigate the role of TNFR2 in microglia and monocytes/macrophages in experimental autoimmune encephalomyelitis (EAE), a model of MS, by cell-specific gene targeting. We show that TNFR2 ablation in microglia leads to early onset of EAE with increased leukocyte infiltration, T cell activation, and demyelination in the central nervous system (CNS). Conversely, TNFR2 ablation in monocytes/macrophages results in EAE suppression with impaired peripheral T cell activation and reduced CNS T cell infiltration and demyelination. Our work uncovers a dichotomy of function for TNFR2 in myeloid cells, with microglial TNFR2 providing protective signals to contain disease and monocyte/macrophagic TNFR2 driving immune activation and EAE initiation. This must be taken into account when targeting TNFR2 for therapeutic purposes in neuroinflammatory diseases.

KEYWORDS:

TNF signaling; cytokines; macrophages; microglia; multiple sclerosis; neuroinflammation; tumor necrosis factor

PMID:
28052249
PMCID:
PMC5218601
DOI:
10.1016/j.celrep.2016.11.083
[PubMed - in process]
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