6533b7d8fe1ef96bd126adb0

RESEARCH PRODUCT

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

Marco PrinzShizuo AkiraMarkus KnustStefan EndresStefan EndresHeinz WiendlDietmar PfeiferAndrew L. CroxfordGunther HartmannKatrin KierdorfStefanie GauppHendrik PoeckHendrik PoeckAri WaismanSven G. MeuthUlrich KalinkeAngela DannCornelius MaihoeferKlaus-peter Knobeloch

subject

Central Nervous SystemEncephalomyelitis Autoimmune ExperimentalCell SurvivalT-LymphocytesAutoimmunityInflammationStimulationReceptor Interferon alpha-betamedicine.disease_causeAutoimmunityMiceCytosolImmune systemmedicineAnimalsbiologyMicrogliaRIG-IGeneral NeuroscienceMultiple sclerosisHelicaseCell DifferentiationDendritic Cellsmedicine.diseasemedicine.anatomical_structurebiology.proteinmedicine.symptomNeuroscienceRNA Helicases

description

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.

yearjournalcountryeditionlanguage
2011-12-04Nature Neuroscience
https://doi.org/10.1038/nn.2964