期刊
NATURE NEUROSCIENCE
卷 15, 期 1, 页码 98-U126出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.2964
关键词
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资金
- German Research Council (DFG) [KFO177, SFB670, SFB704]
- Bundesministerium fur Bildung und Forschung (BMBF)
- DFG [Graduiertenkolleg 1202, SFB 620, FOR133, PR 577/8-1]
- Center of Integrated Protein Science Munich
- Competence Network of Neurodegenerative Disorders
- Center of Chronic Immunodeficiency (CCI)
- Gemeinnutzige Hertie-Foundation
The action of cytosolic RIG-I-like helicases (RLHs) in the CNS during autoimmunity is largely unknown. Using a mouse model of multiple sclerosis, we found that mice lacking the RLH adaptor IPS-1 developed exacerbated disease that was accompanied by markedly higher inflammation, increased axonal damage and elevated demyelination with increased encephalitogenic immune responses. Furthermore, activation of RLH ligands such as 5'-triphosphate RNA oligonucleotides decreased CNS inflammation and improved clinical signs of disease. RLH stimulation repressed the maintenance and expansion of committed T(H)1 and T(H)17 cells, whereas T-cell differentiation was not altered. Notably, T(H)1 and T(H)17 suppression required type I interferon receptor engagement on dendritic cells, but not on macrophages or microglia. These results identify RLHs as negative regulators of T(H)1 and T(H)17 responses in the CNS, demonstrate a protective role of the RLH pathway for brain inflammation, and establish oligonucleotide ligands of RLHs as potential therapeutics for the treatment of multiple sclerosis.
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