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

Han Gao, Matt C. Danzi, Claire S. Choi, Mehran Taherian, Camilla Dalby-Hansen, Ditte G. Ellman, Pernille M. Madsen, John Bixby, Vance Lemmon, Kate L. Lambertsen, Roberta Brambilla

Research output: Contribution to journalArticle

35 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)198-212
Number of pages15
JournalCell Reports
Volume18
Issue number1
DOIs
StatePublished - Jan 3 2017

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Autoimmune Experimental Encephalomyelitis
Tumor Necrosis Factor Receptors
Chemical activation
Monocytes
Macrophages
Microglia
Neurology
Demyelinating Diseases
Ablation
Infiltration
Multiple Sclerosis
Central Nervous System
Tumor Necrosis Factor-alpha
Receptors, Tumor Necrosis Factor, Type II
Gene Targeting
Myeloid Cells
Leukocytes
Genes

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Opposing Functions of Microglial and Macrophagic TNFR2 in the Pathogenesis of Experimental Autoimmune Encephalomyelitis. / Gao, Han; Danzi, Matt C.; Choi, Claire S.; Taherian, Mehran; Dalby-Hansen, Camilla; Ellman, Ditte G.; Madsen, Pernille M.; Bixby, John; Lemmon, Vance; Lambertsen, Kate L.; Brambilla, Roberta.

In: Cell Reports, Vol. 18, No. 1, 03.01.2017, p. 198-212.

Research output: Contribution to journalArticle

Gao, Han ; Danzi, Matt C. ; Choi, Claire S. ; Taherian, Mehran ; Dalby-Hansen, Camilla ; Ellman, Ditte G. ; Madsen, Pernille M. ; Bixby, John ; Lemmon, Vance ; Lambertsen, Kate L. ; Brambilla, Roberta. / Opposing Functions of Microglial and Macrophagic TNFR2 in the Pathogenesis of Experimental Autoimmune Encephalomyelitis. In: Cell Reports. 2017 ; Vol. 18, No. 1. pp. 198-212.
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