Cytosolic RIG-I–like helicases act as negative regulators of sterile inflammation in the CNS

Nature Neuroscience, 2012, 15, doi:10.1038/nn.2964, 98–106, published on 09.02.2012
Nature Neuroscience, online article
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 TH1 and TH17 cells, whereas T-cell differentiation was not altered. Notably, TH1 and TH17 suppression required type I interferon receptor engagement on dendritic cells, but not on macrophages or microglia. These results identify RLHs as negative regulators of TH1 and TH17 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.  

TU München
Helmholtz München
MPI of Neurobiology
MPI of Biochemistry