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 language | English (US) |
|---|---|
| Pages (from-to) | 198-212 |
| Number of pages | 15 |
| Journal | Cell Reports |
| Volume | 18 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 3 2017 |
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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 journal › Article
}
TY - JOUR
T1 - Opposing Functions of Microglial and Macrophagic TNFR2 in the Pathogenesis of Experimental Autoimmune Encephalomyelitis
AU - Gao, Han
AU - Danzi, Matt C.
AU - Choi, Claire S.
AU - Taherian, Mehran
AU - Dalby-Hansen, Camilla
AU - Ellman, Ditte G.
AU - Madsen, Pernille M.
AU - Bixby, John
AU - Lemmon, Vance
AU - Lambertsen, Kate L.
AU - Brambilla, Roberta
PY - 2017/1/3
Y1 - 2017/1/3
N2 - 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.
AB - 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.
KW - cytokines
KW - macrophages
KW - microglia
KW - multiple sclerosis
KW - neuroinflammation
KW - TNF signaling
KW - tumor necrosis factor
UR - http://www.scopus.com/inward/record.url?scp=85009085859&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85009085859&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2016.11.083
DO - 10.1016/j.celrep.2016.11.083
M3 - Article
C2 - 28052249
AN - SCOPUS:85009085859
VL - 18
SP - 198
EP - 212
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 1
ER -