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Opposing Functions of Microglial and Macrophagic TNFR2 in the Pathogenesis of Experimental Autoimmune Encephalomyelitis
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 experiment...
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Published in: | Cell reports (Cambridge) 2017-01, Vol.18 (1), p.198-212 |
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Main Authors: | , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | 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.
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•TNFR2 has opposing functions in microglia and monocytes/macrophages in EAE•Microglial TNFR2 mediates protective responses at EAE onset•Monocyte/macrophagic TNFR2 is detrimental in EAE by driving autoimmune activation
Gao et al. uncover a dichotomy of functions for microglial versus monocyte/macrophagic TNFR2 in EAE pathophysiology. They demonstrate that TNFR2 in microglia is protective and provides signals to contain neuroinflammation, whereas TNFR2 in monocytes/macrophages is detrimental and drives immune activation and EAE initiation. |
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ISSN: | 2211-1247 2211-1247 |
DOI: | 10.1016/j.celrep.2016.11.083 |