Opposing functions of microglial and macrophagic TNFR2 in the pathogenesis of experimental autoimmune encephalomyelitis

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

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Abstrakt

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.

OriginalsprogEngelsk
TidsskriftCell Reports
Vol/bind18
Udgave nummer1
Sider (fra-til)198-212
ISSN2211-1247
DOI
StatusUdgivet - 3. jan. 2017

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