1. Cytosolic RIG-I-like helicases act as negative regulators of sterile inflammation in the CNS.
- Author
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Dann, Angela, Poeck, Hendrik, Croxford, Andrew L, Gaupp, Stefanie, Kierdorf, Katrin, Knust, Markus, Pfeifer, Dietmar, Maihoefer, Cornelius, Endres, Stefan, Kalinke, Ulrich, Meuth, Sven G, Wiendl, Heinz, Knobeloch, Klaus-Peter, Akira, Shizuo, Waisman, Ari, Hartmann, Gunther, and Prinz, Marco
- Subjects
DNA helicases ,INFLAMMATION ,OLIGONUCLEOTIDES ,LABORATORY mice ,AUTOIMMUNITY ,AXONS ,IMMUNE response - Abstract
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 TH 17 cells, whereas T-cell differentiation was not altered. Notably, TH 1 and TH 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 TH 1 and TH 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. [ABSTRACT FROM AUTHOR]- Published
- 2012
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